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Di Febo R, Saeed Z, Serafini F, Brocco D, D'Ascanio F, Pizzi AD, Tinari N, Crescitelli R, Lanuti P, Renda G. Diagnostic and prognostic roles of endothelial- and platelet-derived extracellular vesicles in cardiovascular diseases. J Transl Med 2025; 23:553. [PMID: 40380176 PMCID: PMC12085008 DOI: 10.1186/s12967-025-06522-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 04/22/2025] [Indexed: 05/19/2025] Open
Abstract
Extracellular vesicles (EVs) are membrane-bound structures released by all cell types. They play a critical role in intercellular communication by transferring their cargo, comprising proteins, lipids, metabolites, RNAs, miRNAs, and DNA fragments, to recipient cells. This transfer influences gene expression, signaling pathways, and cellular behavior. Due to their ability to alter the physiology of recipient cells, EVs hold significant therapeutic potential. Additionally, EVs are implicated in various physiological and pathological processes, including immune regulation, cancer progression, and cardiovascular diseases. EVs have been detected in many biological fluids, such as peripheral blood, saliva, urine, cerebrospinal fluid, and breast milk. The cargo of EVs dynamically reflects the physiological and pathological state of their parent cells, making them promising candidates for liquid biopsies in various clinical conditions. Specifically, different EV subtypes in cardiovascular diseases have been studied, with both endothelial and platelet-derived EVs playing significant roles in cardiovascular pathologies. This review focuses on the diagnostic and prognostic potential of endothelial and platelet-derived EVs in cardiovascular diseases, highlighting the role of EV subpopulations.
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Affiliation(s)
- Riccardo Di Febo
- Department of Health Sciences, University of Milan, Milan, Italy
| | - Zeeba Saeed
- Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy
- Center for Advanced Studies and Technology, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy
| | - Francesco Serafini
- Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy
| | - Davide Brocco
- Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy
- Center for Advanced Studies and Technology, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy
| | - Francesca D'Ascanio
- Center for Advanced Studies and Technology, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy
- Department of Humanities, Law and Economics, Leonardo da Vinci University, 66010, Torrevecchia Teatina (CH), Italy
| | - Andrea Delli Pizzi
- Department of Innovative Technologies in Medicine & Dentistry, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy
- Institute for Advanced Biomedical Technologies, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Nicola Tinari
- Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy
- Center for Advanced Studies and Technology, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy
| | - Rossella Crescitelli
- Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Paola Lanuti
- Center for Advanced Studies and Technology, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy
- Department of Medicine and Aging Science, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy
| | - Giulia Renda
- Center for Advanced Studies and Technology, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy.
- Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy.
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Schwarz G, Ren X, Xie W, Guo H, Jiang Y, Zhang J. Engineered exosomes: a promising drug delivery platform with therapeutic potential. Front Mol Biosci 2025; 12:1583992. [PMID: 40417062 PMCID: PMC12098103 DOI: 10.3389/fmolb.2025.1583992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Accepted: 04/22/2025] [Indexed: 05/27/2025] Open
Abstract
Exosomes, small membranous vesicles naturally secreted by living cells, have garnered attention for their role in intercellular communication and therapeutic potential. Their low immunogenicity, high biocompatibility, and efficient biological barrier penetration make them promising drug delivery vehicles. This review spans research developments from 2010 to 2025, covering the engineering of exosomes to optimize cargo loading and targeting specificity. We discuss their applications in treating cardiovascular diseases, liver fibrosis, immune diseases, and neurological diseases, alongside ongoing clinical trials and industry progress. Future challenges include scalability, standardization, and minimizing off-target effects. We propose strategies to address these hurdles, such as bioengineering techniques and improved isolation methods. By synthesizing current knowledge and outlining future directions, this review aims to guide researchers toward harnessing exosomes for disease treatment.
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Affiliation(s)
- Genevieve Schwarz
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
| | - Xuechen Ren
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, United States
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Haitao Guo
- Department of Microbiology and Molecular Genetics, Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States
| | - Yong Jiang
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
| | - Jinyu Zhang
- Department of Cell and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States
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Li G, Chen H, Shen J, Ding Y, Chen J, Zhang Y, Tang M, Xu N, Fang Y. Unveiling new therapeutic horizons in rheumatoid arthritis: an In-depth exploration of circular RNAs derived from plasma exosomes. J Orthop Surg Res 2025; 20:109. [PMID: 39881399 PMCID: PMC11776339 DOI: 10.1186/s13018-025-05494-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 01/13/2025] [Indexed: 01/31/2025] Open
Abstract
Rheumatoid arthritis (RA), a chronic inflammatory joint disease causing permanent disability, involves exosomes, nanosized mammalian extracellular particles. Circular RNA (circRNA) serves as a biomarker in RA blood samples. This research screened differentially expressed circRNAs in RA patient plasma exosomes for novel diagnostic biomarkers. In this study, samples of RA patients with insufficient response to methotrexate (MTX-IR), combined use of tumor necrosis factor inhibitors (TNFi) were followed up for half a year, and 56 circRNA samples of self-test data were stratified into training, testing, and external validation cohorts according to whether American College of Rheumatology 20% improvement criteria (ACR20) was achieved. A diagnostic xgboost model was developed using common hub genes identified by random forest and least absolute shrinkage and selection operator (LASSO), with intersection genes derived from overlapping machine learning-selected genes. Diagnostic performance evaluated via receiver operating characteristic (ROC) curves using pROC for area under the curve (AUC). Optimal LASSO model with 4 circRNAs determined, with AUC > 0.6 for key genes. The model validation performed well on the test set, but not significantly on the validation set. Then, circRNA screening was performed in combination with clinical data, and cross-validation identified hsa-circ0002715, hsa-circ0001946, hsa-circ0000836, and rheumatoid factor (RF) as key genes, among which hsa-circ0002715 and hsa-circ0001946 were emphasized as key markers on the training set. In addition, the morphology and size of exosomes and the expression of CD9 and CD81 verified the successful extraction of exosomes. The qPCR analysis of plasma exosomes in TNFi patients found that the expression of hsa-circ0002715 was higher than that in patients who didn't reach ACR20, and the expression of hsa-circ0001946 was lower than that in patients who didn't reach ACR20. The above studies suggested that hsa-circ0002715 and hsa-circ0001946 may become markers for predicting MTX-IR RA patients and TNFi precision treatment.
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Affiliation(s)
- Guoqing Li
- Department of Rheumatology and Immunology, Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368 Hanjiang Middle Road, Yangzhou, Jiangsu, 225000, China
| | - Hongyi Chen
- Department of Rheumatology and Immunology, Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368 Hanjiang Middle Road, Yangzhou, Jiangsu, 225000, China
| | - Jiacheng Shen
- Department of Rheumatology and Immunology, Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368 Hanjiang Middle Road, Yangzhou, Jiangsu, 225000, China
| | - Yimin Ding
- Department of Rheumatology and Immunology, Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368 Hanjiang Middle Road, Yangzhou, Jiangsu, 225000, China
| | - Jingqiong Chen
- Department of Rheumatology and Immunology, Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368 Hanjiang Middle Road, Yangzhou, Jiangsu, 225000, China
| | - Yongbin Zhang
- Department of Rheumatology and Immunology, Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368 Hanjiang Middle Road, Yangzhou, Jiangsu, 225000, China
| | - Mingrui Tang
- Department of Rheumatology and Immunology, Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368 Hanjiang Middle Road, Yangzhou, Jiangsu, 225000, China
| | - Nan Xu
- Department of Rheumatology and Immunology, Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368 Hanjiang Middle Road, Yangzhou, Jiangsu, 225000, China
| | - Yuxuan Fang
- Department of Rheumatology and Immunology, Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368 Hanjiang Middle Road, Yangzhou, Jiangsu, 225000, China.
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Hirai K, Sawada R, Hayashi T, Araki T, Nakagawa N, Kondo M, Yasuda K, Hirata T, Sato T, Nakatsuka Y, Yoshida M, Kasahara S, Baba K, Oh H. Eight-Year Outcomes of Cardiosphere-Derived Cells in Single Ventricle Congenital Heart Disease. J Am Heart Assoc 2024; 13:e038137. [PMID: 39526355 DOI: 10.1161/jaha.124.038137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 09/16/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Cardiosphere-derived cell (CDC) infusion was associated with better clinical outcomes at 2 years in patients with single ventricle heart disease. The current study investigates time-to-event outcomes at 8 years. METHODS AND RESULTS This cohort enrolled patients with single ventricles who underwent stage 2 or stage 3 palliation from January 2011 to January 2015 at 8 centers in Japan. The primary outcomes were time-dependent CDC treatment effects on death and late complications during 8 years of follow-up, assessed by restricted mean survival time. Among 93 patients enrolled (mean age, 2.3±1.3 years; 56% men), 40 received CDC infusion. Overall survival for CDC-treated versus control patients did not differ at 8 years (hazard ratio [HR], 0.60 [95% CI, 0.21-1.77]; P=0.35). Treatment effect had nonproportional hazards for death favoring CDCs at 4 years (restricted mean survival time difference +0.33 years [95% CI, 0.01-0.66]; P=0.043). In patients with heart failure with reduced ejection fraction, CDC treatment effect on survival was greater over 8 years (restricted mean survival time difference +1.58 years [95% CI, 0.05-3.12]; P=0.043). Compared with control participants, CDC-treated patients showed lower incidences of late failure (HR, 0.45 [95% CI, 0.21-0.93]; P=0.027) and adverse events (subdistribution HR, 0.50 [95% CI, 0.27-0.94]; P=0.036) at 8 years. CONCLUSIONS By 8 years, CDC infusion was associated with lower hazards of late failure and adverse events in single ventricle heart disease. CDC treatment effect on survival was notable by 4 years and showed a durable clinical benefit in patients with heart failure with reduced ejection fraction over 8 years. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01273857 and NCT01829750.
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Affiliation(s)
- Kenta Hirai
- Department of Pediatrics Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Japan
- Department of Regenerative Medicine, Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan
| | - Ryusuke Sawada
- Department of Pharmacology Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Japan
| | - Tomohiro Hayashi
- Department of Pediatrics Kurashiki Central Hospital Okayama Japan
| | - Toru Araki
- Department of Pediatrics National Hospital Organization Fukuyama Medical Center Hiroshima Japan
| | - Naomi Nakagawa
- Department of Pediatric Cardiology Hiroshima City Hiroshima Citizens Hospital Hiroshima Japan
| | - Maiko Kondo
- Department of Pediatrics Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Japan
- Department of Pediatrics Kochi Health Sciences Center Kochi Japan
| | - Kenji Yasuda
- Department of Pediatrics Shimane University Faculty of Medicine Izumo Shimane Japan
| | - Takuya Hirata
- Department of Pediatrics Kyoto University Graduate School of Medicine Kyoto Japan
| | - Tomoyuki Sato
- Department of Pediatrics Jichi Medical University Tochigi Japan
| | - Yuki Nakatsuka
- Department of Data Science, Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan
| | - Michihiro Yoshida
- Department of Data Science, Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan
| | - Shingo Kasahara
- Department of Cardiovascular Surgery Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Japan
| | - Kenji Baba
- Department of Pediatrics Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama Japan
| | - Hidemasa Oh
- Department of Regenerative Medicine, Center for Innovative Clinical Medicine Okayama University Hospital Okayama Japan
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Cui X, Guo J, Yuan P, Dai Y, Du P, Yu F, Sun Z, Zhang J, Cheng K, Tang J. Bioderived Nanoparticles for Cardiac Repair. ACS NANO 2024; 18:24622-24649. [PMID: 39185722 DOI: 10.1021/acsnano.3c07878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Biobased therapy represents a promising strategy for myocardial repair. However, the limitations of using live cells, including the risk of immunogenicity of allogeneic cells and inconsistent therapeutic efficacy of autologous cells together with low stability, result in an unsatisfactory clinical outcomes. Therefore, cell-free strategies for cardiac tissue repair have been proposed as alternative strategies. Cell-free strategies, primarily based on the paracrine effects of cellular therapy, have demonstrated their potential to inhibit apoptosis, reduce inflammation, and promote on-site cell migration and proliferation, as well as angiogenesis, after an infarction and have been explored preclinically and clinically. Among various cell-free modalities, bioderived nanoparticles, including adeno-associated virus (AAV), extracellular vesicles, cell membrane-coated nanoparticles, and exosome-mimetic nanovesicles, have emerged as promising strategies due to their improved biological function and therapeutic effect. The main focus of this review is the development of existing cellular nanoparticles and their fundamental working mechanisms, as well as the challenges and opportunities. The key processes and requirements for cardiac tissue repair are summarized first. Various cellular nanoparticle modalities are further highlighted, together with their advantages and limitations. Finally, we discuss various delivery approaches that offer potential pathways for researchers and clinicians to translate cell-free strategies for cardiac tissue repair into clinical practice.
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Affiliation(s)
- Xiaolin Cui
- Cardiac and Osteochondral Tissue Engineering (COTE) Group, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Jiacheng Guo
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Peiyu Yuan
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Yichen Dai
- Cardiac and Osteochondral Tissue Engineering (COTE) Group, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Pengchong Du
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Fengyi Yu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Zhaowei Sun
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Jinying Zhang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Ke Cheng
- Department of Biomedical Engineering, Columbia University, New York, New York 10027, United States
| | - Junnan Tang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
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Gu Y, Feng J, Shi J, Xiao G, Zhang W, Shao S, Liu B, Guo H. Global Research Trends on Exosome in Cardiovascular Diseases: A Bibliometric-Based Visual Analysis. Vasc Health Risk Manag 2024; 20:377-402. [PMID: 39188326 PMCID: PMC11346494 DOI: 10.2147/vhrm.s473520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 08/10/2024] [Indexed: 08/28/2024] Open
Abstract
Background Exosomes in cardiovascular diseases (CVDs) have attracted huge attention with substantial value and potential. Our bibliometrics is based on literature from the field of cardiovascular exosomes over the past 30 years, which has been visualized to display the development process, research hotspots, and cutting-edge trends of clinical practices, mechanisms, and management strategies related to psych cardiology. Methods We selected articles and reviews on exosomes in CVDs from the core collection of Web of Science, and generated visual charts by using CiteSpace and VOSviewer software. Results Our research included 1613 publications. The number of exosome articles in CVD fluctuates slightly, but overall shows an increasing trend. The main research institutions were Tongji University and Nanjing Medical University. The International Journal of Molecular Sciences has the highest publication volume, while the Journal of Cellular and Molecular Medicine has the highest citation count. Among all the authors, Eduardo Marban ranks first in terms of publication volume and H-index. The most common keywords are exosome, extracellular vesicles, and angiogenesis. Conclusion This is a bibliometric study on the research hotspots and trends of exosomes in CVD. Exosome research in the field of cardiovascular medicine is on the rise. Some exosome treatment methods may become the focus of future research.
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Affiliation(s)
- Yunxiao Gu
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Jiaming Feng
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Jiayi Shi
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Guanyi Xiao
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Weiwei Zhang
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Shuijin Shao
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Baonian Liu
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Haidong Guo
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
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Karpov OA, Stotland A, Raedschelders K, Chazarin B, Ai L, Murray CI, Van Eyk JE. Proteomics of the heart. Physiol Rev 2024; 104:931-982. [PMID: 38300522 PMCID: PMC11381016 DOI: 10.1152/physrev.00026.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 12/25/2023] [Accepted: 01/14/2024] [Indexed: 02/02/2024] Open
Abstract
Mass spectrometry-based proteomics is a sophisticated identification tool specializing in portraying protein dynamics at a molecular level. Proteomics provides biologists with a snapshot of context-dependent protein and proteoform expression, structural conformations, dynamic turnover, and protein-protein interactions. Cardiac proteomics can offer a broader and deeper understanding of the molecular mechanisms that underscore cardiovascular disease, and it is foundational to the development of future therapeutic interventions. This review encapsulates the evolution, current technologies, and future perspectives of proteomic-based mass spectrometry as it applies to the study of the heart. Key technological advancements have allowed researchers to study proteomes at a single-cell level and employ robot-assisted automation systems for enhanced sample preparation techniques, and the increase in fidelity of the mass spectrometers has allowed for the unambiguous identification of numerous dynamic posttranslational modifications. Animal models of cardiovascular disease, ranging from early animal experiments to current sophisticated models of heart failure with preserved ejection fraction, have provided the tools to study a challenging organ in the laboratory. Further technological development will pave the way for the implementation of proteomics even closer within the clinical setting, allowing not only scientists but also patients to benefit from an understanding of protein interplay as it relates to cardiac disease physiology.
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Affiliation(s)
- Oleg A Karpov
- Smidt Heart Institute, Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
| | - Aleksandr Stotland
- Smidt Heart Institute, Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
| | - Koen Raedschelders
- Smidt Heart Institute, Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
| | - Blandine Chazarin
- Smidt Heart Institute, Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
| | - Lizhuo Ai
- Smidt Heart Institute, Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
| | - Christopher I Murray
- Smidt Heart Institute, Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
| | - Jennifer E Van Eyk
- Smidt Heart Institute, Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States
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Mao L, Liu S, Chen Y, Huang H, Ding F, Deng L. Engineered exosomes: a potential therapeutic strategy for septic cardiomyopathy. Front Cardiovasc Med 2024; 11:1399738. [PMID: 39006168 PMCID: PMC11239395 DOI: 10.3389/fcvm.2024.1399738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 06/14/2024] [Indexed: 07/16/2024] Open
Abstract
Septic cardiomyopathy, a life-threatening complication of sepsis, can cause acute heart failure and carry a high mortality risk. Current treatments have limitations. Fortunately, engineered exosomes, created through bioengineering technology, may represent a potential new treatment method. These exosomes can both diagnose and treat septic cardiomyopathy, playing a crucial role in its development and progression. This article examines the strategies for using engineered exosomes to protect cardiac function and treat septic cardiomyopathy. It covers three innovative aspects: exosome surface modification technology, the use of exosomes as a multifunctional drug delivery platform, and plant exosome-like nanoparticle carriers. The article highlights the ability of exosomes to deliver small molecules, proteins, and drugs, summarizing several RNA molecules, proteins, and drugs beneficial for treating septic cardiomyopathy. Although engineered exosomes are a promising biotherapeutic carrier, they face challenges in clinical application, such as understanding the interaction mechanism with host cells, distribution within the body, metabolism, and long-term safety. Further research is essential, but engineered exosomes hold promise as an effective treatment for septic cardiomyopathy.
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Affiliation(s)
- Lixia Mao
- Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Songtao Liu
- Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yongxia Chen
- Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Huiyi Huang
- Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Fenghua Ding
- Outpatient Appointment Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Liehua Deng
- Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Liu DZ, Luo XZ, Lu CH, Feng YY, Chen DX, Zeng ZY, Huang F. Y4 RNA fragments from cardiosphere-derived cells ameliorate diabetic myocardial ischemia‒reperfusion injury by inhibiting protein kinase C β-mediated macrophage polarization. Cardiovasc Diabetol 2024; 23:202. [PMID: 38867293 PMCID: PMC11170846 DOI: 10.1186/s12933-024-02247-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 04/22/2024] [Indexed: 06/14/2024] Open
Abstract
The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune and inflammatory cells, potentially driven by abnormalities in their number and function due to diabetes, may play a significant role. In the present investigation, we simulated myocardial I/R injury by inducing ischemia through ligation of the left anterior descending coronary artery in mice for 40 min, followed by reperfusion for 24 h. Previous studies have indicated that protein kinase Cβ (PKCβ) is upregulated under hyperglycemic conditions and is implicated in the development of various diabetic complications. The Y4 RNA fragment is identified as the predominant small RNA component present in the extracellular vesicles of cardio sphere-derived cells (CDCs), exhibiting notable anti-inflammatory properties in the contexts of myocardial infarction and cardiac hypertrophy. Our investigation revealed that the administration of Y4 RNA into the ventricular cavity of db/db mice following myocardial I/R injury markedly enhanced cardiac function. Furthermore, Y4 RNA was observed to facilitate M2 macrophage polarization and interleukin-10 secretion through the suppression of PKCβ activation. The mechanism by which Y4 RNA affects PKCβ by regulating macrophage activation within the inflammatory environment involves the inhibition of ERK1/2 phosphorylation In our study, the role of PKCβ in regulating macrophage polarization during myocardial I/R injury was investigated through the use of PKCβ knockout mice. Our findings indicate that PKCβ plays a crucial role in modulating the inflammatory response associated with macrophage activation in db/db mice experiencing myocardial I/R, with a notable exacerbation of this response observed upon significant upregulation of PKCβ expression. In vitro studies further elucidated the protective mechanism by which Y4 RNA modulates the PKCβ/ERK1/2 signaling pathway to induce M2 macrophage activation. Overall, our findings suggest that Y4 RNA plays an anti-inflammatory role in diabetic I/R injury, suggesting a novel therapeutic approach for managing myocardial I/R injury in diabetic individuals.
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Affiliation(s)
- De-Zhao Liu
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Xiao-Zhi Luo
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Chuang-Hong Lu
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Yang-Yi Feng
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - De-Xin Chen
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, Guangxi, China
| | - Zhi-Yu Zeng
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, Guangxi, China.
| | - Feng Huang
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, No.6 Shuangyong Road, Nanning, 530021, Guangxi, China.
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10
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Gareev I, Beylerli O, Ilyasova T, Ahmad A, Shi H, Chekhonin V. Therapeutic application of adipose-derived stromal vascular fraction in myocardial infarction. iScience 2024; 27:109791. [PMID: 38736548 PMCID: PMC11088339 DOI: 10.1016/j.isci.2024.109791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/14/2024] Open
Abstract
The insufficiency of natural regeneration processes in higher organisms, including humans, underlies myocardial infarction (MI), which is one of the main causes of disability and mortality in the population of developed countries. The solution to this problem lies in the field of revealing the mechanisms of regeneration and creating on this basis new technologies for stimulating endogenous regenerative processes or replacing lost parts of tissues and organs with transplanted cells. Of great interest is the use of the so-called stromal vascular fraction (SVF), derived from autologous adipose tissue. It is known that the main functions of SVF are angiogenetic, antiapoptotic, antifibrotic, immune regulation, anti-inflammatory, and trophic. This study presents data on the possibility of using SVF, targeted regulation of its properties and reparative potential, as well as the results of research studies on its use for the restoration of damaged ischemic tissue after MI.
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Affiliation(s)
- Ilgiz Gareev
- Bashkir State Medical University, Ufa 450008, Russian Federation
| | - Ozal Beylerli
- Bashkir State Medical University, Ufa 450008, Russian Federation
| | - Tatiana Ilyasova
- Bashkir State Medical University, Ufa 450008, Russian Federation
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Huaizhang Shi
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin 1500, China
| | - Vladimir Chekhonin
- Pirogov Russian National Research Medical University of the Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
- Serbsky Federal Medical Research Centre of Psychiatry and Narcology of the Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
- The National Medical Research Center for Endocrinology, Moscow, Russian Federation
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11
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Silver BB, Kreutz A, Weick M, Gerrish K, Tokar EJ. Biomarkers of chemotherapy-induced cardiotoxicity: toward precision prevention using extracellular vesicles. Front Oncol 2024; 14:1393930. [PMID: 38706609 PMCID: PMC11066856 DOI: 10.3389/fonc.2024.1393930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 04/02/2024] [Indexed: 05/07/2024] Open
Abstract
Detrimental side effects of drugs like doxorubicin, which can cause cardiotoxicity, pose barriers for preventing cancer progression, or treating cancer early through molecular interception. Extracellular vesicles (EVs) are valued for their potential as biomarkers of human health, chemical and molecular carcinogenesis, and therapeutics to treat disease at the cellular level. EVs are released both during normal growth and in response to toxicity and cellular death, playing key roles in cellular communication. Consequently, EVs may hold promise as precision biomarkers and therapeutics to prevent or offset damaging off-target effects of chemotherapeutics. EVs have promise as biomarkers of impending cardiotoxicity induced by chemotherapies and as cardioprotective therapeutic agents. However, EVs can also mediate cardiotoxic cues, depending on the identity and past events of their parent cells. Understanding how EVs mediate signaling is critical toward implementing EVs as therapeutic agents to mitigate cardiotoxic effects of chemotherapies. For example, it remains unclear how mixtures of EV populations from cells exposed to toxins or undergoing different stages of cell death contribute to signaling across cardiac tissues. Here, we present our perspective on the outlook of EVs as future clinical tools to mitigate chemotherapy-induced cardiotoxicity, both as biomarkers of impending cardiotoxicity and as cardioprotective agents. Also, we discuss how heterogeneous mixtures of EVs and transient exposures to toxicants may add complexity to predicting outcomes of exogenously applied EVs. Elucidating how EV cargo and signaling properties change during dynamic cellular events may aid precision prevention of cardiotoxicity in anticancer treatments and development of safer chemotherapeutics.
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Affiliation(s)
- Brian B. Silver
- Mechanistic Toxicology Branch, Division of Translational Toxicology (DTT), National Institute of Environmental Health Sciences (NIEHS), Durham, NC, United States
- Molecular Genomics Core, Division of Intramural Research (DIR), National Institute of Environmental Health Sciences (NIEHS), Durham, NC, United States
| | - Anna Kreutz
- Mechanistic Toxicology Branch, Division of Translational Toxicology (DTT), National Institute of Environmental Health Sciences (NIEHS), Durham, NC, United States
- Epigenetics & Stem Cell Biology Laboratory, Division of Intramural Research (DIR), National Institute of Environmental Health Sciences (NIEHS), Durham, NC, United States
- Inotiv, Durham, NC, United States
| | - Madeleine Weick
- Molecular Genomics Core, Division of Intramural Research (DIR), National Institute of Environmental Health Sciences (NIEHS), Durham, NC, United States
| | - Kevin Gerrish
- Molecular Genomics Core, Division of Intramural Research (DIR), National Institute of Environmental Health Sciences (NIEHS), Durham, NC, United States
| | - Erik J. Tokar
- Mechanistic Toxicology Branch, Division of Translational Toxicology (DTT), National Institute of Environmental Health Sciences (NIEHS), Durham, NC, United States
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12
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Gong ZT, Xiong YY, Ning Y, Tang RJ, Xu JY, Jiang WY, Li XS, Zhang LL, Chen C, Pan Q, Hu MJ, Xu J, Yang YJ. Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway. Int J Nanomedicine 2024; 19:2005-2024. [PMID: 38469055 PMCID: PMC10926597 DOI: 10.2147/ijn.s441307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 02/18/2024] [Indexed: 03/13/2024] Open
Abstract
Background Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI). Methods MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism. Results Compared to MSC-exo, MSCNIC-exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68+ CD206+/ CD68+cells in infarcted hearts 3 days post-infarction. The notable ability of MSCNIC-exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSCNIC-exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway. Conclusion This study suggested that MSCNIC-exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.
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Affiliation(s)
- Zhao-Ting Gong
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
| | - Yu-Yan Xiong
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Yu Ning
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
| | - Rui-Jie Tang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
| | - Jun-Yan Xu
- Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China
| | - Wen-Yang Jiang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
| | - Xiao-Song Li
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
| | - Li-Li Zhang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
| | - Cheng Chen
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
| | - Qi Pan
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
| | - Meng-Jin Hu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
| | - Jing Xu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
| | - Yue-Jin Yang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China
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13
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Li X, Ji LJ, Feng KD, Huang H, Liang MR, Cheng SJ, Meng XD. Emerging role of exosomes in ulcerative colitis: Targeting NOD-like receptor family pyrin domain containing 3 inflammasome. World J Gastroenterol 2024; 30:527-541. [PMID: 38463022 PMCID: PMC10921143 DOI: 10.3748/wjg.v30.i6.527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/21/2023] [Accepted: 01/09/2024] [Indexed: 02/05/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease. Despite ongoing advances in our understanding of UC, its pathogenesis is yet unelucidated, underscoring the urgent need for novel treatment strategies for patients with UC. Exosomes are nanoscale membrane particles that mediate intercellular communication by carrying various bioactive molecules, such as proteins, RNAs, DNA, and metabolites. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic tripartite protein complex whose activation induces the maturation and secretion of proinflammatory cytokines interleukin-1β (IL-1β) and IL-18, triggering the inflammatory response to a pathogenic agent or injury. Growing evidence suggests that exosomes are new modulators of the NLRP3 inflammasome, with vital roles in the pathological process of UC. Here, recent evidence is reviewed on the role of exosomes and NLRP3 inflammasome in UC. First, the dual role of exosomes on NLRP3 inflammasome and the effect of NLRP3 inflammasome on exosome secretion are summarized. Finally, an outlook on the directions of exosome-NLRP3 inflammasome crosstalk research in the context of UC is proposed and areas of further research on this topic are highlighted.
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Affiliation(s)
- Xin Li
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
| | - Li-Jiang Ji
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Kai-Di Feng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hua Huang
- Department of Anorectal Surgery, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu 215500, Jiangsu Province, China
| | - Mei-Rou Liang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shi-Jin Cheng
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xiu-Dong Meng
- School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
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14
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Rajan EJE, Alwar SV, Gulati R, Rajiv R, Mitra T, Janardhanan R. Prospecting the theragnostic potential of the psycho-neuro-endocrinological perturbation of the gut-brain-immune axis for improving cardiovascular diseases outcomes. Front Mol Biosci 2024; 10:1330327. [PMID: 38333633 PMCID: PMC10850560 DOI: 10.3389/fmolb.2023.1330327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 12/22/2023] [Indexed: 02/10/2024] Open
Abstract
Biological derivatives and their effective influence on psychological parameters are increasingly being deciphered to better understand body-mind perspectives in health. Recent evidence suggests that the gut-brain immune axis is an attractive theragnostic target due to its innate capacity to excite the immune system by activating monocyte exosomes. These exosomes induce spontaneous alterations in the microRNAs within the brain endothelial cells, resulting in an acute inflammatory response with physiological and psychological sequelae, evidenced by anxiety and depression. Exploring the role of the stress models that influence anxiety and depression may reflect on the effect and role of exosomes, shedding light on various physiological responses that explain the contributing factors of cardiovascular disorders. The pathophysiological effects of gut-microbiome dysbiosis are further accentuated by alterations in the glucose metabolism, leading to type 2 diabetes, which is known to be a risk factor for cardiovascular disorders. Understanding the role of exosomes and their implications for cell-to-cell communication, inflammatory responses, and neuronal stress reactions can easily provide insight into the gut-brain immune axis and downstream cardiovascular sequelae.
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Affiliation(s)
- Emilda Judith Ezhil Rajan
- Department of Clinical Psychology, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, India
| | - Sai Varsaa Alwar
- Researcher, Division of Medical Research, Faculty of Medical and Health Sciences, SRM IST, Kattankulathur, India
| | - Richa Gulati
- Researcher, Division of Medical Research, Faculty of Medical and Health Sciences, SRM IST, Kattankulathur, India
| | - Rohan Rajiv
- Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PaA, United States
| | - Tridip Mitra
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, India
| | - Rajiv Janardhanan
- Division of Medical Research, Faculty of Medicine and Health Sciences, SRM Institute of Science and Technology, Kattankulathur, India
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15
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Huang C, Han X, Yang L, Song W, Zhang H, Zhu X, Huang G, Xu J. Exosomal miR-129 and miR-342 derived from intermittent hypoxia-stimulated vascular smooth muscle cells inhibit the eIF2α/ATF4 axis from preventing calcified aortic valvular disease. J Cell Commun Signal 2023:10.1007/s12079-023-00785-4. [PMID: 37812275 DOI: 10.1007/s12079-023-00785-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 09/01/2023] [Indexed: 10/10/2023] Open
Abstract
This study aims to elucidate the role of miR-129/miR-342 loaded in exosomes derived from vascular smooth muscle cells (VSMCs) stimulated by intermittent hypoxia in calcified aortic valvular disease (CAVD). Bioinformatics analysis was conducted to identify differentially expressed miRs in VSMCs-derived exosomes and CAVD samples, and their potential target genes were predicted. VSMCs were exposed to intermittent hypoxia to induce stimulation, followed by isolation of exosomes. Valvular interstitial cells (VICs) were cultured in vitro to investigate the impact of miR-129/miR-342 on VICs' osteogenic differentiation and aortic valve calcification with eIF2α. A CAVD mouse model was established using ApoE knockout mice for in vivo validation. In CAVD samples, miR-129 and miR-342 were downregulated, while eIF2α and ATF4 were upregulated. miR-129 and miR-342 exhibited inhibitory effects on eIF2α through targeted regulation. Exosomes released from intermittently hypoxia-stimulated VSMCs contained miR-129 and miR-342. Overexpression of miR-129 and miR-342, or silencing ATF4, suppressed VICs' osteogenic differentiation and aortic valve calcification, which could be rescued by overexpressed eIF2α. Collectively, intermittent hypoxia stimulation of VSMCs leads to the secretion of exosomes that activate the miR-129/miR-342 dual pathway, thereby inhibiting the eIF2α/ATF4 axis and attenuating VICs' osteogenic differentiation and CAVD progression.
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Affiliation(s)
- Chen Huang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Erqi Distrcit, Zhengzhou, 450000, Henan Province, China
| | - Xu Han
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Erqi Distrcit, Zhengzhou, 450000, Henan Province, China
| | - Linjie Yang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Erqi Distrcit, Zhengzhou, 450000, Henan Province, China
| | - Wei Song
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Erqi Distrcit, Zhengzhou, 450000, Henan Province, China
| | - Hualu Zhang
- Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300070, China
| | - Xiaohua Zhu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Erqi Distrcit, Zhengzhou, 450000, Henan Province, China
| | - Gongcheng Huang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Erqi Distrcit, Zhengzhou, 450000, Henan Province, China
| | - Jing Xu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Zhengzhou University, No.1, Jianshe East Road, Erqi Distrcit, Zhengzhou, 450000, Henan Province, China.
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16
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Ponchia PI, Ahmed R, Farag M, Alkhalil M. Antiplatelet Therapy in End-stage Renal Disease Patients on Maintenance Dialysis: a State-of-the-art Review. Cardiovasc Drugs Ther 2023; 37:975-987. [PMID: 35867319 DOI: 10.1007/s10557-022-07366-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/06/2022] [Indexed: 11/03/2022]
Abstract
Patients with end-stage renal disease (ESRD) on maintenance dialysis have an increased risk of ischaemic events, such as recurrent myocardial infarction (MI) and stroke. Potent antiplatelet therapy may help mitigate this risk. Nonetheless, ERSD patients are also at increased risk of bleeding due to their complex vascular milieu, which limits the routine use of potent P2Y12 inhibitors. Moreover, these patients are often underrepresented or excluded from major clinical trials leaving a significant gap in existing knowledge. Understanding the mechanisms of this paradox may serve as a benchmark for the development of ESRD trials. The present review aims to provide an overview of the pathophysiological nature of increased bleeding and ischaemic risks in ERSD patients as well as summarize available evidence of antiplatelet use and propose new concepts to guide physicians in selecting appropriate drug regimes for this high-risk cohort.
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Affiliation(s)
| | | | - Mohamed Farag
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Mohammad Alkhalil
- Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, NE7 7DN, UK.
- Department of Cardiothoracic Services, Freeman Hospital, Freeman Road, Newcastle-upon-Tyne, NE7 7DN, UK.
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17
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Li N, Zhang T, Zhu L, Sun L, Shao G, Gao J. Recent Advances of Using Exosomes as Diagnostic Markers and Targeting Carriers for Cardiovascular Disease. Mol Pharm 2023; 20:4354-4372. [PMID: 37566627 DOI: 10.1021/acs.molpharmaceut.3c00268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2023]
Abstract
Cardiovascular diseases (CVDs) are the leading cause of human death worldwide. Exosomes act as endogenous biological vectors; they possess advantages of low immunogenicity and low safety risks, also providing tissue selectivity, including the inherent targeting the to heart. Therefore, exosomes not only have been applied as biomarkers for diagnosis and therapeutic outcome confirmation but also showed potential as drug carriers for cardiovascular targeting delivery. This review aims to summarize the progress and challenges of exosomes as novel biomarkers, especially many novel exosomal noncoding RNAs (ncRNAs), and also provides an overview of the improved targeting functions of exosomes by unique engineered approaches, the latest developed administration methods, and the therapeutic effects of exosomes used as the biocarriers of medications for cardiovascular disease treatment. Also, the possible therapeutic mechanisms and the potentials for transferring exosomes to the clinic for CVD treatment are discussed. The advances, in vivo and in vitro applications, modifications, mechanisms, and challenges summarized in this review will provide a general understanding of this promising strategy for CVD treatment.
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Affiliation(s)
- Ni Li
- Department of Cardiothoracic Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315041, China
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Tianyuan Zhang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Linwen Zhu
- Department of Cardiothoracic Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315041, China
| | - Lebo Sun
- Department of Cardiothoracic Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315041, China
| | - Guofeng Shao
- Department of Cardiothoracic Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315041, China
| | - Jianqing Gao
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
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18
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Yuan YG, Wang JL, Zhang YX, Li L, Reza AMMT, Gurunathan S. Biogenesis, Composition and Potential Therapeutic Applications of Mesenchymal Stem Cells Derived Exosomes in Various Diseases. Int J Nanomedicine 2023; 18:3177-3210. [PMID: 37337578 PMCID: PMC10276992 DOI: 10.2147/ijn.s407029] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 05/31/2023] [Indexed: 06/21/2023] Open
Abstract
Exosomes are nanovesicles with a wide range of chemical compositions used in many different applications. Mesenchymal stem cell-derived exosomes (MSCs-EXOs) are spherical vesicles that have been shown to mediate tissue regeneration in a variety of diseases, including neurological, autoimmune and inflammatory, cancer, ischemic heart disease, lung injury, and liver fibrosis. They can modulate the immune response by interacting with immune effector cells due to the presence of anti-inflammatory compounds and are involved in intercellular communication through various types of cargo. MSCs-EXOs exhibit cytokine storm-mitigating properties in response to COVID-19. This review discussed the potential function of MSCs-EXOs in a variety of diseases including neurological, notably epileptic encephalopathy and Parkinson's disease, cancer, angiogenesis, autoimmune and inflammatory diseases. We provided an overview of exosome biogenesis and factors that regulate exosome biogenesis. Additionally, we highlight the functions and potential use of MSCs-EXOs in the treatment of the inflammatory disease COVID-19. Finally, we covered a strategies and challenges of MSCs-EXOs. Finally, we discuss conclusion and future perspectives of MSCs-EXOs.
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Affiliation(s)
- Yu-Guo Yuan
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
- Jiangsu Co-Innovation Center of Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
| | - Jia-Lin Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
- Jiangsu Co-Innovation Center of Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
| | - Ya-Xin Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
- Jiangsu Co-Innovation Center of Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
| | - Ling Li
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
- Jiangsu Co-Innovation Center of Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China
| | - Abu Musa Md Talimur Reza
- Department of Molecular Biology and Genetics, Faculty of Science, Gebze Technical University, Gebze, Kocaeli, Türkiye
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19
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Li X, Cao Y, Xu X, Wang C, Ni Q, Lv X, Yang C, Zhang Z, Qi X, Song G. Sleep Deprivation Promotes Endothelial Inflammation and Atherogenesis by Reducing Exosomal miR-182-5p. Arterioscler Thromb Vasc Biol 2023; 43:995-1014. [PMID: 37021573 DOI: 10.1161/atvbaha.123.319026] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/22/2023] [Indexed: 04/07/2023]
Abstract
BACKGROUND Insufficient or disrupted sleep increases the risk of cardiovascular disease, including atherosclerosis. However, we know little about the molecular mechanisms by which sleep modulates atherogenesis. This study aimed to explore the potential role of circulating exosomes in endothelial inflammation and atherogenesis under sleep deprivation status and the molecular mechanisms involved. METHODS Circulating exosomes were isolated from the plasma of volunteers with or without sleep deprivation and mice subjected to 12-week sleep deprivation or control littermates. miRNA array was performed to determine changes in miRNA expression in circulating exosomes. RESULTS Although the total circulating exosome levels did not change significantly, the isolated plasma exosomes from sleep-deprived mice or human were a potent inducer of endothelial inflammation and atherogenesis. Through profiling and functional analysis of the global microRNA in the exosomes, we found miR-182-5p is a key exosomal cargo that mediates the proinflammatory effects of exosomes by upregulation of MYD88 (myeloid differentiation factor 88) and activation of NF-ĸB (nuclear factor kappa-B)/NLRP3 pathway in endothelial cells. Moreover, sleep deprivation or the reduction of melatonin directly decreased the synthesis of miR-182-5p and led to the accumulation of reactive oxygen species in small intestinal epithelium. CONCLUSIONS The findings illustrate an important role for circulating exosomes in distant communications, suggesting a new mechanism underlying the link between sleep disorder and cardiovascular disease.
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Affiliation(s)
- Xiao Li
- School of Basic Medical Sciences, and The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Science, Jinan, China (X.L., Y.C., X.X., C.W., X.L., C.Y., Z.Z., G.S.)
| | - Ying Cao
- School of Basic Medical Sciences, and The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Science, Jinan, China (X.L., Y.C., X.X., C.W., X.L., C.Y., Z.Z., G.S.)
| | - Xinxin Xu
- School of Basic Medical Sciences, and The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Science, Jinan, China (X.L., Y.C., X.X., C.W., X.L., C.Y., Z.Z., G.S.)
| | - Chongyue Wang
- School of Basic Medical Sciences, and The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Science, Jinan, China (X.L., Y.C., X.X., C.W., X.L., C.Y., Z.Z., G.S.)
| | - Qingbin Ni
- Hydrogen medicine center, Tai 'an City Central Hospital, China (Q.N.)
| | - Xiang Lv
- School of Basic Medical Sciences, and The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Science, Jinan, China (X.L., Y.C., X.X., C.W., X.L., C.Y., Z.Z., G.S.)
| | - Chao Yang
- School of Basic Medical Sciences, and The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Science, Jinan, China (X.L., Y.C., X.X., C.W., X.L., C.Y., Z.Z., G.S.)
| | - Zhaoqiang Zhang
- School of Basic Medical Sciences, and The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Science, Jinan, China (X.L., Y.C., X.X., C.W., X.L., C.Y., Z.Z., G.S.)
| | - Xufeng Qi
- Key Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan University, Guangzhou, China (X.Q.)
| | - Guohua Song
- School of Basic Medical Sciences, and The Second Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Science, Jinan, China (X.L., Y.C., X.X., C.W., X.L., C.Y., Z.Z., G.S.)
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20
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Yang SY, Deng WW, Zhao RZ, Long XP, Wang DM, Guo HH, Jiang LX, Chen WM, Shi B. Exosomes Derived from Endothelial Cells Inhibit Neointimal Hyperplasia Induced by Carotid Artery Injury in Rats via ROS-NLRP3 Inflammasome Pathway. Bull Exp Biol Med 2023; 174:762-767. [PMID: 37162629 DOI: 10.1007/s10517-023-05788-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Indexed: 05/11/2023]
Abstract
This study attempted to investigate whether exosomes derived from rat endothelial cells (EC-Exo) attenuate intimal hyperplasia after balloon injury using hematoxylin and eosin staining, immunohistochemistry, immunofluorescence staining, Evans blue staining, and Western blotting. The results indicated that EC-Exo inhibited intimal hyperplasia in the carotid artery after balloon injury, promoted re-endothelialization, and reduced vascular inflammation and ROS-NLRP3-mediated cell pyroptosis. Thus, EC-Exo can inhibit neointimal hyperplasia after carotid artery injury in rats presumably by inhibiting the ROS-NLRP3 inflammasome and phenotypic transformation of vascular smooth muscle cells.
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Affiliation(s)
- S Y Yang
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - W W Deng
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - R Z Zhao
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - X P Long
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - D M Wang
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - H H Guo
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - L X Jiang
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - W M Chen
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - B Shi
- Department of Cardiology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
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21
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Lu W, Liu X, Zhao L, Yan S, Song Q, Zou C, Li X. MiR-22-3p in exosomes increases the risk of heart failure after down-regulation of FURIN. Chem Biol Drug Des 2023; 101:550-567. [PMID: 36063111 DOI: 10.1111/cbdd.14142] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 09/02/2022] [Accepted: 09/02/2022] [Indexed: 11/30/2022]
Abstract
Heart failure (HF) is often the inevitable manifestation of myocardial ischemia. Hypoxia can induce cardiomyocytes to express many microRNAs (miRNAs), which are highly expressed in exosomes. In addition, miR-22-3p is a marker in heart failure. Therefore, miR-22-3p was taken as the research object to explore its role and mechanism in HF. HF differentially expressed miRNAs were screened by bioinformatic analysis. The HF rats model was constructed and identified by detecting serum brain natriuretic peptide (BNP) and ultrasound analysis [left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS)]. The extracted exosomes were identified by transmission electron microscopy, and Western blot was used to detect the expressions of Tsg101 and CD63. Quantitative real-time polymerase chain reaction detected miR-22-3p expression in serum, exosomes, and serum without exosomes, while the cardiomyocytes cytotoxicity was detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and PKH26 staining. After overexpressing/silencing miR-22-3p in cells, cell viability, apoptosis, and apoptosis-associated markers were detected. Bioinformatic analysis screened the target gene of miR-22-3p, which was verified by dual-luciferase assay. Regulation of miR-22-3p on FURIN was measured by rescue tests. In vivo experiments were verified the above results. MiR-22-3p was identified as the research object. BNP was increased in the model group, while LVEF and LVFS were decreased. MiR-22-3p was overexpressed in HF-treated serum and exosomes. Normal exosomes did not affect cardiomyocyte function, while high concentrations of HF-treated exosomes were cytotoxic. By regulating apoptosis-related genes, overexpressed miR-22-3p inhibited cell activity and promoted cell apoptosis. Silenced miR-22-3p with opposite effects counteracted effects of HF-treated exosomes. FURIN, target gene of miR-22-3p, was negatively regulated by miR-22-3p, while overexpressed FURIN promoted cell activity and inhibited apoptosis. In vivo research was consistent with the results of cell experiments. By regulating FURIN, miR-22-3p in exosomes increases the risk of HF damage.
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Affiliation(s)
- Wenlin Lu
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China.,Department of Cardiovascular Medicine, Wuxi No. 2 People's Hospital, Wuxi, China
| | - Xuhui Liu
- Department of Cardiovascular Medicine, Huai'an Second People's Hospital, Huai'an, China
| | - Linghui Zhao
- Department of Cardiovascular Medicine, Huaiyin Hospital of Huai'an City, Huai'an, China
| | - Shirong Yan
- Department of Cardiovascular Medicine, Huaiyin Hospital of Huai'an City, Huai'an, China
| | - Qingyun Song
- Department of Cardiovascular Medicine, Huaiyin Hospital of Huai'an City, Huai'an, China
| | - Cao Zou
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xun Li
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China
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22
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Tong X, Zhao X, Dang X, Kou Y, Kou J. circRNA, a novel diagnostic biomarker for coronary heart disease. Front Cardiovasc Med 2023; 10:1070616. [PMID: 36818340 PMCID: PMC9928865 DOI: 10.3389/fcvm.2023.1070616] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 01/05/2023] [Indexed: 02/04/2023] Open
Abstract
Objective This study aimed to identify the potential diagnostic biomarkers of coronary heart disease (CHD) from exosome-derived circRNA. Methods The microarray data of circRNA derived from the exosomes of patients with CHD and mRNA in acute myocardial infarction was retrieved from exoRBase website and GEO database (GSE61144), respectively, to identify the differentially expressed genes (DEGs). Our findings detected the differentially expressed circRNAs and mRNAs and predicted their correlation with microRNAs using the microRNA target prediction website, thus ascertaining the corresponding circ-microRNA and micro-mRNAs. Then, we performed systematic Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on the differentially expressed mRNA. Protein-Protein Interactions (PPI) of these DEGs were examined using STRING. The receiver operator characteristic (ROC) curve was used to validate the diagnostic efficacy of circRNA in patients with CHD. Finally, the RNAs identified in this study were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Results A total of 85 differentially expressed circRNAs (4 up-regulated and 81 down-regulated) were identified by screening the circRNAs in exosome of CHD patients. Based on the prediction data of circRNA, mRNA, and the corresponding microRNA, a ceRNA network was constructed, including 7 circRNA nodes, 5 microRNA nodes, and 2 mRNA nodes. Finally, validated by qRT-PCR testing, we found circRNA0001785, circRNA0000973, circRNA0001741, and circRNA0003922 to be the promising candidate for the effective prediction of CHD. These potential diagnostic markers can provide insight for further research on the occurrence of CHD or even acute coronary syndrome (ACS).
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23
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Sylvén C, Wärdell E, Månsson-Broberg A, Cingolani E, Ampatzis K, Larsson L, Björklund Å, Giacomello S. High cardiomyocyte diversity in human early prenatal heart development. iScience 2022; 26:105857. [PMID: 36624836 PMCID: PMC9823232 DOI: 10.1016/j.isci.2022.105857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/19/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022] Open
Abstract
Cardiomyocytes play key roles during cardiogenesis, but have poorly understood features, especially in prenatal stages. Here, we characterized human prenatal cardiomyocytes, 6.5-7 weeks post-conception, by integrating single-cell RNA sequencing, spatial transcriptomics, and ligand-receptor interaction information. Using a computational workflow developed to dissect cell type heterogeneity, localize cell types, and explore their molecular interactions, we identified eight types of developing cardiomyocyte, more than double compared to the ones identified in the Human Developmental Cell Atlas. These have high variability in cell cycle activity, mitochondrial content, and connexin gene expression, and are differentially distributed in the ventricles, including outflow tract, and atria, including sinoatrial node. Moreover, cardiomyocyte ligand-receptor crosstalk is mainly with non-cardiomyocyte cell types, encompassing cardiogenesis-related pathways. Thus, early prenatal human cardiomyocytes are highly heterogeneous and develop unique location-dependent properties, with complex ligand-receptor crosstalk. Further elucidation of their developmental dynamics may give rise to new therapies.
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Affiliation(s)
- Christer Sylvén
- Department of Medicine, Karolinska Institute, Huddinge, Sweden,Corresponding author
| | - Eva Wärdell
- Department of Medicine, Karolinska Institute, Huddinge, Sweden
| | | | | | | | - Ludvig Larsson
- Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Åsa Björklund
- Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Stefania Giacomello
- Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden,Corresponding author
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24
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Zhang Q, Chen L, Huang L, Cheng H, Wang L, Xu L, Hu D, He C, Fu C, Wei Q. CD44 promotes angiogenesis in myocardial infarction through regulating plasma exosome uptake and further enhancing FGFR2 signaling transduction. Mol Med 2022; 28:145. [PMID: 36463112 PMCID: PMC9719212 DOI: 10.1186/s10020-022-00575-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 11/14/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Since angiogenesis occurs as the pathological process following myocardial infarction to alleviate ischemia, therapeutic angiogenesis has been proposed to be a cardioprotective strategy. CD44 has been implicated in endothelial cell functions and its role has been well established in angiogenesis for years. Although recent studies indicate the close correlation between CD44 and exosome, as well as the two being implicated in myocardial ischemia pathological processes, the effect and the underlying mechanism of CD44 and its regulated plasma exosome in pathological angiogenesis post-myocardial infarction have not been fully elucidated. METHODS In this study, we used CD44 knockout mice to study the in vivo impacts of CD44 on ischemic angiogenesis in myocardial infarction. Mouse cardiac function was measured by echocardiography, histological changes were observed by Evans Blue and TTC-double staining and Masson's trichrome staining, and molecular changes were detected by immunofluorescence. In the in vitro study, CD44 knockout HUVECs were generated and CD44 inhibitor was used to study the mechanism of CD44 on angiogenesis. We performed the immunoprecipitation, proximity ligation assay, and super-resolution imaging to study the mechanistic regulation of FGFR2 signaling transduction by CD44. Importantly, we also isolated plasma exosomes from myocardial infarction model mice and studied the effect of plasma exosomes on the activation of the FGFR2 signaling pathway and the related phenotypic alterations, including exosomes uptake and angiogenic function in primary mouse microvascular endothelial cells, and further discovered the regulation mechanism of exosomal miRNAs. RESULTS We observed that the expression of CD44 in the border zone of the infarcted heart was tightly related to pathological angiogenesis following myocardial ischemia. The depletion of CD44 impaired angiogenesis and impacts biogenesis and proangiogenic function of plasma exosomes. Subsequently, we found that CD44 mediated the activation of the FGFR2 signaling pathway as well as the caveolin 1-dependent uptake of exosomes in vascular endothelial cells. Most importantly, the proangiogenic therapeutic effect of plasma exosomal miRNAs depended upon the participation of CD44/FGFR2 signaling transduction in vascular endothelial cells. CONCLUSION CD44 and its regulated plasma exosomes have crucial potent angiogenic activity. Our studies elucidate that CD44 plays a key role in plasma exosomal miRNA-enhanced angiogenic FGFR2 singling transduction and ischemic angiogenesis in the early stage of myocardial infarction.
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Affiliation(s)
- Qing Zhang
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Li Chen
- grid.415440.0Department of Rehabilitation Medicine, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan People’s Republic of China
| | - Liyi Huang
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Hongxin Cheng
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Lu Wang
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Lin Xu
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Danrong Hu
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Chengqi He
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Chenying Fu
- grid.13291.380000 0001 0807 1581National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,grid.13291.380000 0001 0807 1581Aging and Geriatric Mechanism Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China
| | - Quan Wei
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
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25
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An Z, Tian J, Liu Y, Zhao X, Yang X, Yong J, Liu L, Zhang L, Jiang W, Song X, Zhang H. Exosomes as a Cell-free Therapy for Myocardial Injury Following Acute Myocardial Infarction or Ischemic Reperfusion. Aging Dis 2022; 13:1770-1786. [PMID: 36465167 PMCID: PMC9662265 DOI: 10.14336/ad.2022.0416] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/16/2022] [Indexed: 08/13/2023] Open
Abstract
Exosomes, which contain miRNA, have been receiving growing attention in cardiovascular therapy because of their role in mediating cell-cell communication, autophagy, apoptosis, inflammation, and angiogenesis. Several studies have suggested that miRNA derived from exosomes can be used to detect myocardial infarctions (MI) in patients. Basic research also suggests that exosomes could serve as a potential therapeutic target for treating acute myocardial infarction. Ischemia/reperfusion (IR) injury is associated with adverse cardiac events after acute MI. We aim to review the potential benefits and mechanisms of exosomes in treating MI and IR injury.
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Affiliation(s)
- Ziyu An
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Jinfan Tian
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Yue Liu
- Cardiovascular disease center, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Xin Zhao
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Xueyao Yang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Jingwen Yong
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Libo Liu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Lijun Zhang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Wenjian Jiang
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Xiantao Song
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Hongjia Zhang
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
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26
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Stability of exosomes in the postmortem serum and preliminary study on exosomal miRNA expression profiling in serum from myocardial infarction cadavers. Int J Legal Med 2022; 137:825-834. [PMID: 36416963 DOI: 10.1007/s00414-022-02913-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 11/15/2022] [Indexed: 11/24/2022]
Abstract
Exosome-encapsulated miRNAs could potentially be sensitive biomarkers of human diseases. Since a lipid bilayer membrane surrounds exosomes, the exosomal miRNA may stably exist in body fluids with diseases as well as biological fluids. Therefore, exosomal miRNA may be helpful for autopsy diagnosis. Assuming cadaver blood would be most useful, we initially examined serum exosome stability with regard to storage temperatures and periods. Characteristic analyses of the exosome revealed that exosomes and the content, miRNA, were stably preserved until at least three days when stored at below 20 °C. Subsequently, exosomal miRNA expression profiling was performed on the serum of acute myocardial infarction (AMI, 4 cases) autopsy bodies and on hemorrhagic shock bodies used as the control (CT, 3 cases). Results showed that significant twofold up- and downregulations of expression of 18 and 16 miRNAs were detectable in AMI as compared to the CT, respectively. miR-126-3p, which has been reported to be increased in serum of AMI patients and a mouse model, was one of the significantly upregulated miRNAs. Furthermore, dysregulation of exosomal miRNAs, such as miR-145-5p, miR-143-3p, and miR-222-3p, which are involved in cardioprotection, may be associated with AMI pathogenesis. These findings provide a novel perspective on the potential role of exosomal miRNA in determining the cause of death.
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27
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Khan FB, Uddin S, Elderdery AY, Goh KW, Ming LC, Ardianto C, Palakot AR, Anwar I, Khan M, Owais M, Huang CY, Daddam JR, Khan MA, Shoaib S, Khursheed M, Reshadat S, Khayat Kashani HR, Mirza S, Khaleel AA, Ayoub MA. Illuminating the Molecular Intricacies of Exosomes and ncRNAs in Cardiovascular Diseases: Prospective Therapeutic and Biomarker Potential. Cells 2022; 11:3664. [PMID: 36429092 PMCID: PMC9688392 DOI: 10.3390/cells11223664] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/29/2022] [Accepted: 11/01/2022] [Indexed: 11/19/2022] Open
Abstract
Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide. Accumulating evidences have highlighted the importance of exosomes and non-coding RNAs (ncRNAs) in cardiac physiology and pathology. It is in general consensus that exosomes and ncRNAs play a crucial role in the maintenance of normal cellular function; and interestingly it is envisaged that their potential as prospective therapeutic candidates and biomarkers are increasing rapidly. Considering all these aspects, this review provides a comprehensive overview of the recent understanding of exosomes and ncRNAs in CVDs. We provide a great deal of discussion regarding their role in the cardiovascular system, together with providing a glimpse of ideas regarding strategies exploited to harness their potential as a therapeutic intervention and prospective biomarker against CVDs. Thus, it could be envisaged that a thorough understanding of the intricacies related to exosomes and ncRNA would seemingly allow their full exploration and may lead clinical settings to become a reality in near future.
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Affiliation(s)
- Farheen Badrealam Khan
- Department of Biology, College of Science, The United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
| | - Abozer Y. Elderdery
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72388, Saudi Arabia
| | - Khang Wen Goh
- Faculty of Data Sciences and Information Technology, INTI International University, Nilai 78100, Malaysia
| | - Long Chiau Ming
- PAPRSB Institute of Health Sciences, Universiti Brunei Darussalam, Gadong BE1410, Brunei
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Chrismawan Ardianto
- Department of Pharmacy Practice, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia
| | - Abdul Rasheed Palakot
- Department of Biology, College of Science, The United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Irfa Anwar
- Department of Biology, College of Science, The United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Mohsina Khan
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Mohammad Owais
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, UP, India
| | - Chih-Yang Huang
- Department of Biotechnology, Asia University, Taichung 404, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
- Centre of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan
| | - Jayasimha Rayalu Daddam
- Department of Ruminant Science, Institute of Animal Sciences, Agriculture Research Organization, Volcani Center, Rishon Lezion 7505101, Israel
| | - Meraj Alam Khan
- Program in Translational Medicine, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children & DigiBiomics Inc, Toronto, ON M51X8, Canada
| | - Shoaib Shoaib
- Department Biochemistry, Jawaharlal Nehru Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh 202002, UP, India
| | - Md Khursheed
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai 505055, United Arab Emirates
| | - Sara Reshadat
- Department of Internal Medicine, Semnan University of Medical Sciences, Semnan 3513119111, Iran
| | | | - Sameer Mirza
- Department of Chemistry, United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Abbas A. Khaleel
- Department of Chemistry, United Arab Emirates University, Al Ain 15551, United Arab Emirates
| | - Mohammed Akli Ayoub
- Department of Biology, College of Science, The United Arab Emirates University, Al Ain 15551, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Al Ain 15551, United Arab Emirates
- Department of Biology, College of Arts and Sciences, Khalifa University, Abu Dhabi 127788, United Arab Emirates
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28
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Mesenchymal Stem Cell-Derived Extracellular Vesicles Therapy for Pulmonary Hypertension: A Comprehensive Review of Preclinical Studies. J Interv Cardiol 2022; 2022:5451947. [PMID: 36419957 PMCID: PMC9652076 DOI: 10.1155/2022/5451947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 10/09/2022] [Accepted: 10/20/2022] [Indexed: 11/06/2022] Open
Abstract
Pulmonary hypertension (PH) is a type of clinical pathophysiological syndrome characterized by a progressive increase in pulmonary vascular resistance and subsequent progressive failure of the right heart function, and is a common complication of many diseases. Mesenchymal stem cells (MSCs) autonomously home to sites damaged by disease, repair damaged tissues, and participate in the regulation of systemic inflammation and immune responses, which have good clinical application prospects. Extracellular vesicles (EVs), such as exosomes and microvesicles, participate in various biological activities by regulating intercellular communication. Exosomes secreted into the extracellular environment also affect the host immune system. MSC-derived extracellular vesicles (MSC-EVs), as a mediator in the paracrine processes of MSCs, carry biologically active substances such as proteins, lipids, mRNA, and micro-RNA. MSC-EVs therapies, safer than cell-based treatments, have been shown to be effective in modulating macrophages to support anti-inflammatory phenotypes, which are strongly related to histological and functional benefits in preclinical models of pulmonary hypertension. The main effects of active substances and their potential medical value have attracted wide attention from researchers. This article reviews the role and relevant mechanisms of MSC-EVs in the treatment of pulmonary hypertension in recent studies and provides a basis for their future clinical applications.
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Gu Z, Yin H, Zhang H, Zhang H, Liu X, Zeng X, Zheng X. Optimization of a method for the clinical detection of serum exosomal miR-940 as a potential biomarker of breast cancer. Front Oncol 2022; 12:956167. [PMID: 36338741 PMCID: PMC9634127 DOI: 10.3389/fonc.2022.956167] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 10/05/2022] [Indexed: 10/20/2023] Open
Abstract
Serum exosomal microRNAs (miRNAs) are potential biomarkers for tumor diagnosis. Clinically, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) can be used to determine the expression of exosomal miRNAs in the serum of breast cancer patients. The prerequisites for obtaining meaningful serum exosomal miRNA data of breast cancer patients include a suitable extraction method for exosomes and RT-qPCR data standardized by internal reference genes. However, the appropriate methods for the extraction of exosomes and the applicability of reference genes for analyzing exosomal miRNAs in breast cancer patients remain to be studied. This study compared the effects of three exosome extraction methods as well as the expression of exosomal miRNA in different initial serum amounts and at different serum states to identify the selection of the best method for serum exosome extraction. Five candidate reference genes including miR-16, miR-484, miR-1228, miR-191 and miR-423 for standardizing serum exosomal miRNAs were screened using five algorithms and were used for the quantification of serum exosomal miR-940. Significant downregulation of serum exosomal miR-940 expression in breast cancer was detected using miR-191 and miR-1228, whereas no significant down or up regulation was observed with miR-484, miR-423 and miR-16. Previous studies have shown that the expression level of miR-940 is downregulated in breast cancer tissues. The absolute quantitative results showed that miR-940 was significantly downregulated in breast cancer serum exosomes, which was consistent with the results from the analysis using miR-191 or miR-1228 as reference genes. Therefore, miR-191 and miR-1228 could serve as reference genes for the relative quantification of serum exosomal miRNAs. This finding indicated the importance of rigorously evaluating the stability of reference genes and standardization for serum exosomal miRNA expression. Moreover, the level of serum exosomal miR-940 in breast cancer could reflect the presence of lymph node metastasis and the status of HER2/neu, which indicates its potential as a biomarker for breast cancer metastasis. In summary, an optimized protocol for the detection of serum exosomal miR-940 as a breast cancer marker was preliminarily established.
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Affiliation(s)
- Zhiyun Gu
- Department of Oncology Laboratory, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Haojie Yin
- Bioengineering College, Chongqing University, Chongqing, China
| | - Haiwei Zhang
- Department of Oncology Laboratory, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Hui Zhang
- Department of Oncology Laboratory, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Xiaoyu Liu
- Department of Oncology Laboratory, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Xiaohua Zeng
- Department of Oncology Laboratory, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Xiaodong Zheng
- Department of Oncology Laboratory, Chongqing University Cancer Hospital, Chongqing, China
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
- Medical College of Chongqing University, Chongqing University, Chongqing, China
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Deng W, Wang X, Chen L, Wen B, Chen Y, Ji K, Liu H. Proteomic and miRNA Profiles of Exosomes Derived from Myometrial Tissue in Laboring Women. Int J Mol Sci 2022; 23:ijms232012343. [PMID: 36293200 PMCID: PMC9603981 DOI: 10.3390/ijms232012343] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/30/2022] [Accepted: 10/12/2022] [Indexed: 11/16/2022] Open
Abstract
Myometrial contraction is essential for successful delivery. Recent studies have highlighted the vital roles of tissue-derived exosomes in disease diagnostic, prognostic, and therapeutic applications; however, the characteristics of uterine myometrium-derived exosomes are unclear. Here, we successfully isolated exosomes from myometrial tissues, human myometrial smooth muscle cells (HMSMCs), and human umbilical vein endothelial cells (HUVECs), then performed quantitative liquid chromatography-tandem mass spectrometry and miRNA sequencing to investigate the cargo of the exosomes. Fifty-two proteins and five miRNAs were differentially expressed (DE) in term non-labor and term labor myometrium-derived exosomes. Among them, seven proteins (SERPINE1, THBS1, MGAT1, VIM, FGB, FGG, and VWF) were differentially expressed both in the myometrial exosomes and tissues, three miRNAs (miR-363-3p, miR-203a-3p, and miR-205-5p) target 13 DE genes. The top three miRNA derived from HMSMCs (miR-125b-1-3p, miR-337-5p, and miR-503-5p) and HUVECs (miR-663a, miR-4463, and miR-3622a-5p) were identified. Two proteins, GJA1 and SLC39A14, exist in female blood exosomes and are highly expressed in HMSMCs exosomes, are also upregulated in the laboring myometrium, which verified increased in laboring blood samples, might be novel potential biomarkers for myometrial activation. The proteomic and miRNA profile of exosomes derived from laboring myometrium revealed some molecules in the exosomes that affect the intercellular communication and the function of the myometrium.
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Affiliation(s)
- Wenfeng Deng
- Guangzhou Key Laboratory of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Xiaodi Wang
- Guangzhou Key Laboratory of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Lina Chen
- Guangzhou Key Laboratory of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
- School of Medicine, South China University of Technology, Guangzhou 510006, China
| | - Bolun Wen
- Guangzhou Key Laboratory of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Yunshan Chen
- Guangzhou Key Laboratory of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Kaiyuan Ji
- Guangzhou Key Laboratory of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
- Correspondence: (K.J.); (H.L.)
| | - Huishu Liu
- Guangzhou Key Laboratory of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, China
- Correspondence: (K.J.); (H.L.)
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Yao J, Cai L, Chen Y, Zhang J, Zhuang W, Liang J, Li H. Exosomes: mediators regulating the phenotypic transition of vascular smooth muscle cells in atherosclerosis. Cell Commun Signal 2022; 20:153. [PMID: 36221105 PMCID: PMC9555104 DOI: 10.1186/s12964-022-00949-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/31/2022] [Indexed: 11/10/2022] Open
Abstract
Cardiovascular disease is one of the leading causes of human mortality worldwide, mainly due to atherosclerosis (AS), and the phenotypic transition of vascular smooth muscle cells (VSMCs) is a key event in the development of AS. Exosomes contain a variety of specific nucleic acids and proteins that mediate intercellular communication. The role of exosomes in AS has attracted attention. This review uses the VSMC phenotypic transition in AS as the entry point, introduces the effect of exosomes on AS from different perspectives, and discusses the status quo, deficiencies, and potential future directions in this field to provide new ideas for clinical research and treatment of AS. Video Abstract.
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Affiliation(s)
- Jiali Yao
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Linqian Cai
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Yingrui Chen
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Jie Zhang
- Department of Neurology, Afliated Hospital of Yangzhou University, Yangzhou, 225001, China
| | - Wenwen Zhuang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Jingyan Liang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China.,Jiangsu Key Laboratory of Experimental and Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, 225009, Jiangsu, China
| | - Hongliang Li
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, China. .,Jiangsu Key Laboratory of Experimental and Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, 225009, Jiangsu, China.
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Mo C, Zhao J, Liang J, Wang H, Chen Y, Huang G. Exosomes: A novel insight into traditional Chinese medicine. Front Pharmacol 2022; 13:844782. [PMID: 36105201 PMCID: PMC9465299 DOI: 10.3389/fphar.2022.844782] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 07/22/2022] [Indexed: 11/13/2022] Open
Abstract
Exosomes are small extracellular vesicles and play an essential role in the mediation of intercellular communication both in health and disease. Traditional Chinese medicine (TCM) has historically been used to maintain human health and treat various diseases up till today. The interplay between exosomes and TCM has attracted researchers’ growing attention. By integrating the available evidence, TCM formulas and compounds isolated from TCM as exosome modulators have beneficial effects on multiple disorders, such as tumors, kidney diseases, and hepatic disease, which may associate with inhibiting cells proliferation, anti-inflammation, anti-oxidation, and attenuating fibrosis. Exosomes, a natural delivery system, are essential in delivering compounds isolated from TCM to target cells or tissues. Moreover, exosomes may be the potential biomarkers for TCM syndromes, providing strategies for TCM treatment. These findings may provide a novel insight into TCM from exosomes and serve as evidence for better understanding and development of TCM.
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Affiliation(s)
- Chao Mo
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
- Department of Nephrology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, China
| | - Jie Zhao
- Graduate School, Hunan University of Chinese Medicine, Changsha, China
| | - Jingyan Liang
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - Huiling Wang
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - Yu Chen
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - Guodong Huang
- Department of Nephrology, Guangxi International Zhuang Medicine Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
- *Correspondence: Guodong Huang,
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Extracellular Vesicles, Inflammation, and Cardiovascular Disease. Cells 2022; 11:cells11142229. [PMID: 35883672 PMCID: PMC9320258 DOI: 10.3390/cells11142229] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular disease is a leading cause of death worldwide. The underlying mechanisms of most cardiovascular disorders involve innate and adaptive immune responses, and extracellular vesicles are implicated in both. In this review, we describe the mechanistic role of extracellular vesicles at the intersection of inflammatory processes and cardiovascular disease. Our discussion focuses on atherosclerosis, myocardial ischemia and ischemic heart disease, heart failure, aortic aneurysms, and valvular pathology.
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Xiong Y, Tang R, Xu J, Jiang W, Gong Z, Zhang L, Ning Y, Huang P, Xu J, Chen G, Li X, Hu M, Xu J, Wu C, Jin C, Li X, Qian H, Yang Y. Tongxinluo-pretreated mesenchymal stem cells facilitate cardiac repair via exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway. Stem Cell Res Ther 2022; 13:289. [PMID: 35799283 PMCID: PMC9264662 DOI: 10.1186/s13287-022-02969-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 02/21/2022] [Indexed: 12/14/2022] Open
Abstract
Background Bone marrow cells (BMCs), especially mesenchymal stem cells (MSCs), have shown attractive application prospects in acute myocardial infarction (AMI). However, the weak efficacy becomes their main limitation in clinical translation. Based on the anti-inflammation and anti-apoptosis effects of a Chinese medicine-Tongxinluo (TXL), we aimed to explore the effects of TXL-pretreated MSCs (MSCsTXL) in enhancing cardiac repair and further investigated the underlying mechanism. Methods MSCsTXL or MSCs and the derived exosomes (MSCsTXL-exo or MSCs-exo) were collected and injected into the infarct zone of rat hearts. In vivo, the anti-apoptotic and anti-inflammation effects, and cardiac functional and histological recovery were evaluated. In vitro, the apoptosis was evaluated by western blotting and flow cytometry. miRNA sequencing was utilized to identify the significant differentially expressed miRNAs between MSCsTXL-exo and MSCs-exo, and the miRNA mimics and inhibitors were applied to explore the specific mechanism. Results Compared to MSCs, MSCsTXL enhanced cardiac repair with reduced cardiomyocytes apoptosis and inflammation at the early stage of AMI and significantly improved left ventricular ejection fraction (LVEF) with reduced infarct size in an exosome-dependent way. Similarly, MSCsTXL-exo exerted superior therapeutic effects in anti-apoptosis and anti-inflammation, as well as improving LVEF and reducing infarct size compared to MSCs-exo. Further exosomal miRNA analysis demonstrated that miR-146a-5p was the candidate effector of the superior effects of MSCsTXL-exo. Besides, miR-146a-5p targeted and decreased IRAK1, which inhibited the nuclear translocation of NF-κB p65 thus protecting H9C2 cells from hypoxia injury. Conclusions This study suggested that MSCsTXL markedly facilitated cardiac repair via a new mechanism of the exosomal transfer of miR-146a-5p targeting IRAK1/NF-κB p65 pathway, which has great potential for clinical translation. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02969-y.
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Affiliation(s)
- Yuyan Xiong
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Ruijie Tang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Junyan Xu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Wenyang Jiang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Zhaoting Gong
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Lili Zhang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Yu Ning
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Peisen Huang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Jun Xu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Guihao Chen
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Xiaosong Li
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Mengjin Hu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Jing Xu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Chunxiao Wu
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Chen Jin
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Xiangdong Li
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Haiyan Qian
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China
| | - Yuejin Yang
- State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 10037, China.
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Zhang B, Sun C, Liu Y, Bai F, Tu T, Liu Q. Exosomal miR-27b-3p Derived from Hypoxic Cardiac Microvascular Endothelial Cells Alleviates Rat Myocardial Ischemia/Reperfusion Injury through Inhibiting Oxidative Stress-Induced Pyroptosis via Foxo1/GSDMD Signaling. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8215842. [PMID: 35847592 PMCID: PMC9279077 DOI: 10.1155/2022/8215842] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/10/2022] [Accepted: 05/31/2022] [Indexed: 12/30/2022]
Abstract
Background Exosomes derived from cardiac microvascular endothelial cells (CMECs) under hypoxia can mediate cardiac repair functions and alleviate pyroptosis and oxidative stress during ischemia-reperfusion (I/R) injury. This study is aimed at investigating the effect and mechanism of miR-27b-3p underlying hypoxic CMECs-derived exosomes against I/R injury. Methods CMECs were isolated from the left ventricle of Sprague-Dawley rats, followed by culturing under hypoxic conditions or pretreatment with the miR-27b-3p inhibitor. CMECs-derived exosomes were added into H9C2 cells before hypoxia/reoxygenation (H/R) or injected into the rat heart before I/R injury. An in vivo I/R injury model was established by ligating and releasing the left anterior descending coronary artery. Expression of pyroptosis-related factors was detected using Western blot, and heart infarcted size was determined by the 2,3,5-triphenyl-2H-tetrazpinolium chloride staining method. Dual-Luciferase Reporter assays were performed to analyze the interactions of nmiR-27b-3p-forkhead box O1 (Foxo1) and Gasdermin D- (GSDMD-) Foxo1. Chromatin-immunoprecipitation (ChIP) assays were performed to validate the interactions between forkhead box O1 (Foxo1) and Gasdermin D (GSDMD) and Foxo1-mediated histone acetylation of GSDMD. Results CMECs were successfully identified from left ventricle of Sprague-Dawley rats. The expressions of Foxo1 and pyroptosis-related proteins (GSDMD, NLPR3, cleaved caspase 1, IL-1β, and IL-18) were upregulated in the rat heart after I/R injury. Treatment of CMEC-derived exosomes, especially that under hypoxic conditions, significantly reduced pyroptosis in the rat heart. miR-27b-3p was significantly upregulated in CMEC-derived exosomes under hypoxic conditions, and miR-27b-3p inhibition in exosomes alleviated its cytoprotection and inhibited oxidative stress in H9C2 cells. Treatment with Foxo1 overexpression plasmids aggravated in vitro H/R and in vivo I/R injury by upregulating pyroptosis-related proteins. Further experiments validated that miR-27b-3p negatively targeted Foxo1, which bound to the promoter region of GSDMD. Conclusions These results demonstrated a great therapeutic efficacy of miR-27b-3p overexpression in hypoxic CMEC-derived exosomes in preventing the development of myocardial damage post I/R injury through inhibiting Foxo1/GSDMD signaling-induced oxidative stress and pyroptosis.
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Affiliation(s)
- Baojian Zhang
- Cardiac Care Unit, Affiliated Hospital of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi City, Xinjiang Uygur Autonomous Region, China
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chao Sun
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yaozhong Liu
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fan Bai
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tao Tu
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiming Liu
- Department of Cardiology/Cardiac Catheterization Lab, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Qi Z, Yan Z, Wang Y, Ji N, Yang X, Zhang A, Li M, Xu F, Zhang J. Ginsenoside Rh2 Inhibits NLRP3 Inflammasome Activation and Improves Exosomes to Alleviate Hypoxia-Induced Myocardial Injury. Front Immunol 2022; 13:883946. [PMID: 35865525 PMCID: PMC9294352 DOI: 10.3389/fimmu.2022.883946] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 06/09/2022] [Indexed: 11/18/2022] Open
Abstract
The inflammatory microenvironment after acute myocardial infarction (MI) is a key limiting factor in the clinical application of stem cell transplantation and paracrine exosome therapy. Qishen Yiqi Pills contain a saponin ingredient called Ginsenoside Rh2 (Rh2) which exhibits a certain therapeutic effect on MI. However, the mechanism by which Rh2 alleviates the inflammatory microenvironment and improves the therapeutic efficiency of exosomes remains enigmatic. Here, we found that Rh2 attenuated the adverse effect of oxygen-glucose deprivation (OGD)-induced cellular injury, an in vitro pathological model of MI. Confocal microscopy revealed that DiI-labeled BMSCs-derived exosomes exhibited an increased homing ability of cardiomyocytes, which, in turn, inhibited the nuclear translocation of NF-κB p65 and NLRP3 inflammasome activation, thereby alleviating the inflammatory microenvironment and further facilitating the homing of exosomes to cardiomyocytes by forming a feed-forward enhancement loop. Additionally, we found that Rh2 could regulate the HMGB1/NF-κB signaling pathway to improve the OGD environment of cardiomyocytes, increasing the efficiency of the feed-forward loop. In conclusion, we found that Rh2 can improve the inflammatory microenvironment by enhancing the protection of exosomes against myocardial injury, providing new insights into the indirect modification of exosomes by Rh2 in MI treatment.
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Affiliation(s)
- Zhongwen Qi
- Postdoctoral Research Station of China Academy of Chinese Medical Sciences, Institute of Gerontology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhipeng Yan
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yueyao Wang
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Nan Ji
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaoya Yang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ao Zhang
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Meng Li
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Fengqin Xu
- Postdoctoral Research Station of China Academy of Chinese Medical Sciences, Institute of Gerontology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Junping Zhang
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Fan J, Ren M, He Y. Diagnostic and Therapeutic Properties of Exosomes in Cardiac Fibrosis. Front Cell Dev Biol 2022; 10:931082. [PMID: 35859903 PMCID: PMC9289295 DOI: 10.3389/fcell.2022.931082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Cardiac fibrosis results from both the differentiation of cardiac fibroblasts and excessive accumulation of extracellular matrix (ECM), leading to myocardial stiffness and reduced compliance of the ventricular wall. The conversion of cardiac fibroblasts to myofibroblasts is the most important initiating step in the process of this pathological cardiac remodeling. It occurs during the progression of many cardiovascular diseases, adversely influencing both the clinical course and outcome of the disease. The pathogenesis is complex and there is no effective treatment. Exosomes are extracellular vesicles that mediate intercellular communication through delivering specific cargoes of functional nucleic acids and proteins derived from particular cell types. Recent studies have found that exosomes play an important role in the diagnosis and treatment of cardiac fibrosis, and is a potential biotherapeutics and drug delivery vectors for the treatment of cardiac fibrosis. The present review aimed to summarize the current knowledge of exosome-related mechanisms underlying cardiac fibrosis and to suggest potential therapy that could be used to treat the condition.
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Affiliation(s)
- Jiwen Fan
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Meng Ren
- Department of Medical Oncology, Jilin Provincial Cancer Hospital, Changchun, China
| | - Yuquan He
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Yuquan He,
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Zhang X, Wu Y, Cheng Q, Bai L, Huang S, Gao J. Extracellular Vesicles in Cardiovascular Diseases: Diagnosis and Therapy. Front Cell Dev Biol 2022; 10:875376. [PMID: 35721498 PMCID: PMC9198246 DOI: 10.3389/fcell.2022.875376] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 05/13/2022] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of global mortality. Therapy of CVDs is still a great challenge since many advanced therapies have been developed. Multiple cell types produce nano-sized extracellular vesicles (EVs), including cardiovascular system-related cells and stem cells. Compelling evidence reveals that EVs are associated with the pathophysiological processes of CVDs. Recently researches focus on the clinical transformation in EVs-based diagnosis, prognosis, therapies, and drug delivery systems. In this review, we firstly discuss the current knowledge about the biophysical properties and biological components of EVs. Secondly, we will focus on the functions of EVs on CVDs, and outline the latest advances of EVs as prognostic and diagnostic biomarkers, and therapeutic agents. Finally, we will introduce the specific application of EVs as a novel drug delivery system and its application in CVDs therapy. Specific attention will be paid to summarize the perspectives, challenges, and applications on EVs’ clinical and industrial transformation.
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Affiliation(s)
- Xiaojing Zhang
- Department of Pharmacy, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China
- *Correspondence: Xiaojing Zhang, ; Jun Gao,
| | - Yuping Wu
- Department of Scientific Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China
| | - Qifa Cheng
- Department of Pharmacy, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China
| | - Liyang Bai
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Shuqiang Huang
- Department of Clinical Medicine, The Sixth Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Jun Gao
- Department of Pharmacy, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, China
- *Correspondence: Xiaojing Zhang, ; Jun Gao,
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Janouskova O, Herma R, Semeradtova A, Poustka D, Liegertova M, Malinska HA, Maly J. Conventional and Nonconventional Sources of Exosomes-Isolation Methods and Influence on Their Downstream Biomedical Application. Front Mol Biosci 2022; 9:846650. [PMID: 35586196 PMCID: PMC9110031 DOI: 10.3389/fmolb.2022.846650] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Despite extensive study of extracellular vesicles (EVs), specifically exosomes (EXs) as biomarkers, important modulators of physiological or pathological processes, or therapeutic agents, relatively little is known about nonconventional sources of EXs, such as invertebrate or plant EXs, and their uses. Likewise, there is no clear information on the overview of storage conditions and currently used isolation methods, including new ones, such as microfluidics, which fundamentally affect the characterization of EXs and their other biomedical applications. The purpose of this review is to briefly summarize conventional and nonconventional sources of EXs, storage conditions and typical isolation methods, widely used kits and new "smart" technologies with emphasis on the influence of isolation techniques on EX content, protein detection, RNA, mRNA and others. At the same time, attention is paid to a brief overview of the direction of biomedical application of EXs, especially in diagnostics, therapy, senescence and aging and, with regard to the current situation, in issues related to Covid-19.
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Affiliation(s)
- Olga Janouskova
- Centre of Nanomaterials and Biotechnology, Faculty of Science, Jan Evangelista University in Ústí Nad Labem, Ústí Nad Labem, Czech Republic
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Liu X, Hu L, Liu F. Mesenchymal stem cell-derived extracellular vesicles for cell-free therapy of ocular diseases. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2022; 3:102-117. [PMID: 39698446 PMCID: PMC11648472 DOI: 10.20517/evcna.2022.08] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/31/2022] [Accepted: 04/18/2022] [Indexed: 12/20/2024]
Abstract
Mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) have noticeably attracted clinicians' attention in treating ocular diseases. As the paracrine factor of MSCs and an alternative for cell-free therapies, MSC-EVs can be conveniently dropped over the ocular surface or diffused through the retina upon intravitreal injection, without increasing the risks of cellular rejection and tumor formation. For clinical translation, a standardized and scalable production, as well as reprogramming the MSC-EVs, are highly encouraged. This review aims to assess the potential approaches for EV production and functional modification, in addition to summarizing the worldwide clinical trials initiated for various physiological systems and the specific biochemical effects of MSC-EVs on the therapy of eye diseases. Recent advances in the therapy of ocular diseases based on MSC-EVs are reviewed, and the associated challenges and prospects are discussed as well.
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Affiliation(s)
- Xiaoling Liu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Liang Hu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Fei Liu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
- Wenzhou Institute, University of Chinese Academy of Science, Wenzhou 325000, Zhejiang, China
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Chen X, Luo Q. Potential clinical applications of exosomes in the diagnosis, treatment, and prognosis of cardiovascular diseases: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:372. [PMID: 35433929 PMCID: PMC9011294 DOI: 10.21037/atm-22-619] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/07/2022] [Indexed: 12/17/2022]
Abstract
Background and Objective Cardiovascular diseases (CVDs) have been one of the most common threats to human health in recent decades. At present, despite many diagnostic, prognostic and therapeutic methods being applied in the clinic, the prevalence of CVDs continues to rise. Therefore, new discovery is needed and exosomes have received extensive attention. Exosomes are extracellular vesicles that enable communication between cells. They are widely distributed in biofluids, suggesting that they may be useful in CVD diagnosis and prognosis. Furthermore, exosomes are ideal drug transporters with relatively high transport efficiency and the capability to target different kinds of tissues. However, the present research concentrates, for the most part, on mechanistic studies with less attention to clinical applications. Methods More than 150 relevant scientific articles from databases like PubMed, Web of Science were screened and analysed for this narrative review. Data of clinical trials are collected from clinicaltrials.gov. Key Content and Findings In this review, we concentrate on different exosomes and CVDs, and we summarize the physiological and pathological roles of CVD-related exosomes. We focused on the role exosomes may have as biomarkers of CVDs, therapeutic opportunities, and possible hurdles to the clinical application of exosomes, aiming to provide a useful reference for its translational use in the CVD field. Conclusions Specific changes in exosome cargos (mainly miRNAs and proteins) are in accordance with the occurrence and development of CVDs including acute myocardial infarction (AMI), arrhythmia, coronary artery disease (CAD), heart failure (HF) and cardiomyopathy, therefore meaningful for diagnosis and prognosis of CVDs. For exosome related therapeutic methods, potential ways consist of direct administration of exosomes, targeting on exosome synthesis, processing and release, and working as adjuvants. All in all, exosomes are expected to serve as meaningful tools in the diagnosis, treatment and prognosis of CVDs.
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Affiliation(s)
- Xuyang Chen
- Joint Program of Nanchang University and Queen Mary University of London, Queen Mary School, Medical Department, Nanchang University, Nanchang, China.,Department of Histology and Embryology, Nanchang University School of Basic Medical Sciences, Nanchang, China
| | - Qi Luo
- Department of Histology and Embryology, Nanchang University School of Basic Medical Sciences, Nanchang, China
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Li Z, Huo X, Chen K, Yang F, Tan W, Zhang Q, Yu H, Li C, Zhou D, Chen H, Zhao B, Wang Y, Chen Z, Du X. Profilin 2 and Endothelial Exosomal Profilin 2 Promote Angiogenesis and Myocardial Infarction Repair in Mice. Front Cardiovasc Med 2022; 9:781753. [PMID: 35479278 PMCID: PMC9036097 DOI: 10.3389/fcvm.2022.781753] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 01/11/2022] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular diseases (CVD) are the leading cause of death worldwide, wherein myocardial infarction (MI) is the most dangerous one. Promoting angiogenesis is a prospective strategy to alleviate MI. Our previous study indicated that profilin 2 (PFN2) may be a novel target associated with angiogenesis. Further results showed higher levels of serum PFN2 and exosomal PFN2 in patients, mice, and pigs with MI. In this study, we explored whether PFN2 and endothelial cell (EC)-derived exosomal PFN2 could increase angiogenesis and be beneficial for the treatment of MI. Serum PFN2, exosomes, and exosomal PFN2 were elevated in rats with MI. PFN2 and exosomes from PFN2-overexpressing ECs (OE-exo) enhanced EC proliferation, migration, and tube formation ability. OE-exo also significantly increased the vessel number in zebrafish and protected the ECs from inflammatory injury. Moreover, OE-exo-treated mice with MI showed improvement in motor ability, ejection fraction, left ventricular shortening fraction, and left ventricular mass, as well as increased vessel numbers in the MI location, and decreased infarction volume. Mechanistically, PI3K might be the upstream regulator of PFN2, while ERK might be the downstream regulator in the PI3K-PFN2-ERK axis. Taken together, our findings demonstrate that PFN2 and exosomal PFN2 promote EC proliferation, migration, and tube formation through the PI3K-PFN2-ERK axis. Exosomal PFN2 may be a valuable target in the repair of MI injury via angiogenesis.
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Affiliation(s)
- Zhenkun Li
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xueyun Huo
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Keyan Chen
- Department of Laboratory Animal Science, China Medical University, Dalian, China
| | - Fenghua Yang
- Guangdong Laboratory Animals Monitoring Institute, Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou, China
| | - Weijiang Tan
- Guangdong Laboratory Animals Monitoring Institute, Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou, China
| | - Qi Zhang
- Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Haixu Yu
- Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Changlong Li
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Deshan Zhou
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Hao Chen
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China
| | - Baoquan Zhao
- State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing, China
| | - Yuan Wang
- Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Zhenwen Chen
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
| | - Xiaoyan Du
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing, China
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Zheng YL, Wang WD, Cai PY, Zheng F, Zhou YF, Li MM, Du JR, Lin S, Lin HL. Stem cell-derived exosomes in the treatment of acute myocardial infarction in preclinical animal models: a meta-analysis of randomized controlled trials. Stem Cell Res Ther 2022; 13:151. [PMID: 35395872 PMCID: PMC8994329 DOI: 10.1186/s13287-022-02833-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/28/2022] [Indexed: 11/10/2022] Open
Abstract
Background Exosomes (EXOs) derived from stem cells have become a potential new treatment for acute myocardial infarction (AMI). However, their impact is still not fully understood. Therefore, we performed this meta-analysis to systematically review the efficacy of EXOs on AMI in preclinical animal models. Methods We searched PubMed, EMBASE, and the Web of Science from September 1, 1980 to September 1, 2021, to retrieve the studies reporting the therapeutic effects of EXOs on AMI animal models. Secondary endpoints include the fractional shortening (FS), infarct size (IS), fibrosis area (FA), the TNF-α, IL-6 and IL-10 levels, the apoptosis rate and the number of autophagic vesicles. Two authors independently screened the articles based on inclusion and exclusion criteria. All statistical analyses were conducted using Stata14.0. Results Ten studies satisfied the inclusion criteria. Pooled analyses demonstrated that the levels of LVEF (WMD = 3.67%; 95% CI 2.28–5.07%; P = 0.000), FS (WMD = 3.69%; 95% CI 2.06–5.33%; P = 0.000), IS (WMD = −4.52%, 95% CI − 7.14 to − 1.9%; P = 0.001), and FA (WMD = −7.04%, 95% CI − 8.74 to − 5.34%; P = 0.000), TNF-α (WMD = −3.09, 95% CI − 5.47 to − 0.72; P = 0.011), TL-6 (WMD = −6.34, 95% CI − 11.2 to − 1.49; P < 0.01), TL-10 (WMD = 6.37, 95% CI 1.53–11.21; P = 0.01), the apoptosis rate (WMD = −8.23, 95% CI − 15.29 to − 1.17; P = 0.000), and the number of autophagic vesicles (WMD = −4.52, 95% CI − 7.43 to − 1.62; P = 0.000). Subgroup analysis showed that the EXOs were derived from HMSCs. Subgroup analysis showed that the EXOs derived from HMSCs, and that exosome therapy immediately after myocardial infarction can better improve the LVEF. Conclusions: EXOs therapy has the potential to improve cardiac function, fibrogenesis, and inflammatory response, as well as reducing cell apoptosis and autophagy in preclinical AMI animal models. This can inform future human clinical trials of EXOs. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02833-z.
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Affiliation(s)
- Yan-Li Zheng
- Department of Cardiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Wan-da Wang
- Department of Cardiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Ping-Yu Cai
- Department of Cardiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Feng Zheng
- Department of Neurosurgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China
| | - Yi-Fan Zhou
- Department of Cardiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Mei-Mei Li
- Department of Cardiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Jing-Ru Du
- Department of Cardiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China
| | - Shu Lin
- Department of Cardiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China. .,Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, China. .,Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia.
| | - Hui-Li Lin
- Department of Cardiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian Province, China.
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Cardioprotective effect of extracellular vesicles derived from ticagrelor-pretreated cardiomyocyte on hyperglycemic cardiomyocytes through alleviation of oxidative and endoplasmic reticulum stress. Sci Rep 2022; 12:5651. [PMID: 35383227 PMCID: PMC8983723 DOI: 10.1038/s41598-022-09627-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 03/21/2022] [Indexed: 12/21/2022] Open
Abstract
Extracellular vesicles (EVs) play important roles in diabetes mellitus (DM) via connecting the immune cell response to tissue injury, besides stimulation to muscle insulin resistance, while DM is associated with increased risks for major cardiovascular complications. Under DM, chronic hyperglycemia, and subsequent increase in the production of reactive oxygen species (ROS) further lead to cardiac growth remodeling and dysfunction. The purinergic drug ticagrelor is a P2Y12 receptor antagonist. Although it is widely used in cardioprotection, the underlying molecular mechanism of its inhibitory effect on diabetic cardiomyopathy is poorly elucidated. Here, we aimed to understand how ticagrelor exerts its cardio-regulatory effects. For this purpose, we investigated the anti-oxidative and cardioprotective effect of EVs derived from ticagrelor-pretreated cardiomyocytes under DM conditions. To mimic DM in cardiomyocytes, we used high glucose incubated H9c2-cells (HG). HG cells were treated with EVs, which were derived from either ticagrelor-pretreated or untreated H9c2-cells. Our results demonstrated that ticagrelor-pretreated H9c2-derived EVs significantly decreased the hyperglycemia-induced aberrant ROS production, prevented the development of apoptosis and ER stress, and alleviated oxidative stress associated miRNA-expression profile. Importantly, EVs derived from ticagrelor-pretreated H9c2-cells enhanced endothelial cell migration and tube formation, suggesting a modulation of the EV profile in cardiomyocytes. Our data, for the first time, indicate that ticagrelor can exert an important regulatory effect on diabetic cardiomyopathy through extracellular vesicular modulation behind its receptor-inhibition-related effects.
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Chimenti I, Picchio V, Pagano F, Schirone L, Schiavon S, D'Ambrosio L, Valenti V, Forte M, di Nonno F, Rubattu S, Peruzzi M, Versaci F, Greco E, Calogero A, De Falco E, Frati G, Sciarretta S. The impact of autophagy modulation on phenotype and survival of cardiac stromal cells under metabolic stress. Cell Death Discov 2022; 8:149. [PMID: 35365624 PMCID: PMC8975847 DOI: 10.1038/s41420-022-00924-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 01/31/2022] [Accepted: 02/17/2022] [Indexed: 01/18/2023] Open
Abstract
Cardiac stromal cells (CSCs) embrace multiple phenotypes and are a contributory factor in tissue homeostasis and repair. They can be exploited as therapeutic mediators against cardiac fibrosis and remodeling, but their survival and cardioprotective properties can be decreased by microenvironmental cues. We evaluated the impact of autophagy modulation by different pharmacological/genetic approaches on the viability and phenotype of murine CSCs, which had been subjected to nutrient deprivation or hyperglycemia, in order to mimic relevant stress conditions and risk factors of cardiovascular diseases. Our results show that autophagy is activated in CSCs by nutrient deprivation, and that autophagy induction by trehalose or autophagy-related protein 7 (ATG7)-overexpression can significantly preserve CSC viability. Furthermore, autophagy induction is associated with a higher proportion of primitive, non-activated stem cell antigen 1 (Sca1)-positive cells, and with a reduced fibrotic fraction (positive for the discoidin domain-containing receptor 2, DDR2) in the CSC pool after nutrient deprivation. Hyperglycemia, on the other hand, is associated with reduced autophagic flux in CSCs, and with a significant reduction in primitive Sca1+ cells. Autophagy induction by adenoviral-mediated ATG7-overexpression maintains a cardioprotective, anti-inflammatory and pro-angiogenic paracrine profile of CSCs exposed to hyperglycemia for 1 week. Finally, autophagy induction by ATG7-overexpression during hyperglycemia can significantly preserve cell viability in CSCs, which were subsequently exposed to nutrient deprivation, reducing hyperglycemia-induced impairment of cell resistance to stress. In conclusion, our results show that autophagy stimulation preserves CSC viability and function in response to metabolic stressors, suggesting that it may boost the beneficial functions of CSCs in cardiac repair mechanisms.
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Affiliation(s)
- Isotta Chimenti
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
- Mediterranea Cardiocentro, Napoli, Italy.
| | - Vittorio Picchio
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Francesca Pagano
- Biochemistry and Cellular Biology Istitute, CNR, Monterotondo, Italy
| | - Leonardo Schirone
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Department of Clinical, Internal Medicine, Anaesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Sonia Schiavon
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Luca D'Ambrosio
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Valentina Valenti
- Haemodynamic and Cardiology Unit, "Santa Maria Goretti" Hospital, Latina, Italy
| | | | | | - Speranza Rubattu
- IRCCS Neuromed, Pozzilli, Italy
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Mariangela Peruzzi
- Mediterranea Cardiocentro, Napoli, Italy
- Department of Clinical, Internal Medicine, Anaesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Francesco Versaci
- Haemodynamic and Cardiology Unit, "Santa Maria Goretti" Hospital, Latina, Italy
- Department of System Medicine, "Tor Vergata" University, Rome, Italy
| | - Ernesto Greco
- Department of Clinical, Internal Medicine, Anaesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Antonella Calogero
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Elena De Falco
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro, Napoli, Italy
| | - Giacomo Frati
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- IRCCS Neuromed, Pozzilli, Italy
| | - Sebastiano Sciarretta
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- IRCCS Neuromed, Pozzilli, Italy
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Mackay CDA, Jadli AS, Fedak PWM, Patel VB. Adventitial Fibroblasts in Aortic Aneurysm: Unraveling Pathogenic Contributions to Vascular Disease. Diagnostics (Basel) 2022; 12:diagnostics12040871. [PMID: 35453919 PMCID: PMC9025866 DOI: 10.3390/diagnostics12040871] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/15/2022] [Accepted: 03/28/2022] [Indexed: 12/21/2022] Open
Abstract
Aortic aneurysm (AA) is a degenerative vascular disease that involves aortic dilatation, and, if untreated, it can lead to rupture. Despite its significant impact on the healthcare system, its multifactorial nature and elusive pathophysiology contribute to limited therapeutic interventions that prevent the progression of AA. Thus, further research into the mechanisms underlying AA is paramount. Adventitial fibroblasts are one of the key constituents of the aortic wall, and they play an essential role in maintaining vessel structure and function. However, adventitial fibroblasts remain understudied when compared with endothelial cells and smooth muscle cells. Adventitial fibroblasts facilitate the production of extracellular matrix (ECM), providing structural integrity. However, during biomechanical stress and/or injury, adventitial fibroblasts can be activated into myofibroblasts, which move to the site of injury and secrete collagen and cytokines, thereby enhancing the inflammatory response. The overactivation or persistence of myofibroblasts has been shown to initiate pathological vascular remodeling. Therefore, understanding the underlying mechanisms involved in the activation of fibroblasts and in regulating myofibroblast activation may provide a potential therapeutic target to prevent or delay the progression of AA. This review discusses mechanistic insights into myofibroblast activation and associated vascular remodeling, thus illustrating the contribution of fibroblasts to the pathogenesis of AA.
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Affiliation(s)
- Cameron D. A. Mackay
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; (C.D.A.M.); (A.S.J.)
- Libin Cardiovascular Institute, University of Calgary, 3330 Hospital Drive NW HMRB-G71, Calgary, AB T2N 4N1, Canada;
| | - Anshul S. Jadli
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; (C.D.A.M.); (A.S.J.)
- Libin Cardiovascular Institute, University of Calgary, 3330 Hospital Drive NW HMRB-G71, Calgary, AB T2N 4N1, Canada;
| | - Paul W. M. Fedak
- Libin Cardiovascular Institute, University of Calgary, 3330 Hospital Drive NW HMRB-G71, Calgary, AB T2N 4N1, Canada;
- Section of Cardiac Surgery, Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
| | - Vaibhav B. Patel
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; (C.D.A.M.); (A.S.J.)
- Libin Cardiovascular Institute, University of Calgary, 3330 Hospital Drive NW HMRB-G71, Calgary, AB T2N 4N1, Canada;
- Correspondence: or ; Tel.: +1-(403)-220-3446
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Zhang Y, Yang N, Huang X, Zhu Y, Gao S, Liu Z, Cao F, Wang Y. Melatonin Engineered Adipose-Derived Biomimetic Nanovesicles Regulate Mitochondrial Functions and Promote Myocardial Repair in Myocardial Infarction. Front Cardiovasc Med 2022; 9:789203. [PMID: 35402545 PMCID: PMC8985816 DOI: 10.3389/fcvm.2022.789203] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 01/31/2022] [Indexed: 12/22/2022] Open
Abstract
Myocardial infarction (MI), one type of ischemic heart disease, is a major cause of disability and mortality worldwide. Currently, extracellular vesicles (EVs) derived from adipose-derived stem cells (ADSC) have been proven to be a potentially promising therapeutic treatment for MI. However, the inconvenience of isolation, the low productivity, and the high cost of EVs greatly limits their application in clinic. In this study, we constructed novel biomimetic ADSC-derived nanovesicles (ADSC NVs) to achieve cell-free therapy for MI. Here, we firstly developed a novel Mel@NVs delivery system consisting of engineered ADSC NVs with melatonin (Mel). Then, the characterization and properties of Mel@NVs were performed. The effect of Mel@NVs on cellular oxidative stress and myocardial infarction repair was conducted. The results showed that Mel@NVs treatment under ischemia mimic condition reduced cell apoptosis from 42.59 ± 2.69% to 13.88 ± 1.77%. Moreover, this novel engineered Mel@NVs could ameliorate excessive ROS generation, promote microvessel formation, and attenuate cardiac fibrosis, which further alleviates mitochondrial dysfunction and finally enhance myocardial repair. Hence, the engineered NVs show a potential strategy for MI therapy.
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Affiliation(s)
- Yang Zhang
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
| | - Ning Yang
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
| | - Xu Huang
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yan Zhu
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Shan Gao
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
| | - Zhongyang Liu
- Department of Orthopedics, The Fourth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Feng Cao
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
- Feng Cao
| | - Yabin Wang
- Department of Cardiology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital and Medical School of Chinese People's Liberation Army, Beijing, China
- *Correspondence: Yabin Wang
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Sato R, Maruyama K, Nemoto E, Sakisaka Y, Suzuki S, Li J, Numazaki K, Tada H, Yamada S. Extracellular Vesicles Derived From Murine Cementoblasts Possess the Potential to Increase Receptor Activator of Nuclear Factor-κB Ligand-Induced Osteoclastogenesis. Front Physiol 2022; 13:825596. [PMID: 35237179 PMCID: PMC8882962 DOI: 10.3389/fphys.2022.825596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/24/2022] [Indexed: 12/14/2022] Open
Abstract
Cementum resorption, unlike bone resorption, is clinically known to occur only with limited pathological stimuli, such as trauma, orthodontic forces, and large apical periodontitis; however, the molecular mechanisms that control osteoclast formation on the cementum surface remain unclear. In this study, we focused on extracellular vesicles (EVs) secreted by cementoblasts and analyzed their effects on osteoclast differentiation. EVs were extracted from the conditioned medium (CM) of the mouse cementoblast cell line OCCM-30. Transmission electron microscopy (TEM) analysis confirmed the presence of EVs with a diameter of approximately 50–200 nm. The effect of the EVs on osteoclast differentiation was examined using the mouse osteoclast progenitor cell line RAW 264.7 with recombinant receptor activator of nuclear factor (NF)-κB ligand (rRANKL) stimulation. EVs enhanced the formation of tartrate-resistant acid phosphatase (TRAP) activity-positive cells upon rRANKL stimulation. EVs also enhanced the induction of osteoclast-associated gene and protein expression in this condition, as determined by real-time PCR and Western blotting, respectively. On the other hand, no enhancing effect of EVs was observed without rRANKL stimulation. A Western blot analysis revealed no expression of receptor activator of NF-κB ligand (RANKL) in EVs themselves. The effect on rRANKL-induced osteoclast differentiation was examined using the CM of cementoblasts in terms of TRAP activity-positive cell formation and osteoclast-associated gene expression. The conditioned medium partly inhibited rRANKL-induced osteoclast differentiation and almost completely suppressed its enhancing effect by EVs. These results indicate that cementoblasts secreted EVs, which enhanced RANKL-induced osteoclast differentiation, and simultaneously produced soluble factors that neutralized this enhancing effect of EVs, implicating this balance in the regulation of cementum absorption. A more detailed understanding of this crosstalk between cementoblasts and osteoclasts will contribute to the development of new therapies for pathological root resorption.
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Affiliation(s)
- Rei Sato
- Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Kentaro Maruyama
- Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Eiji Nemoto
- Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai, Japan
- *Correspondence: Eiji Nemoto,
| | - Yukihiko Sakisaka
- Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Shigeki Suzuki
- Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Jiajun Li
- Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Kento Numazaki
- Division of Orthodontics and Dentofacial Orthopedics, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Hiroyuki Tada
- Division of Oral Immunology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Satoru Yamada
- Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai, Japan
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Zhang W, Chen Z, Qiao S, Chen S, Zheng H, Wei X, Li Q, Xu B, Huang W. The effects of extracellular vesicles derived from Krüppel-Like Factor 2 overexpressing endothelial cells on the regulation of cardiac inflammation in the dilated cardiomyopathy. J Nanobiotechnology 2022; 20:76. [PMID: 35139878 PMCID: PMC8827179 DOI: 10.1186/s12951-022-01284-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 01/23/2022] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Dilated cardiomyopathy (DCM) is one of the common causes of heart failure. Myocardial injury triggers an inflammatory response and recruits immune cells into the heart. High expression of Krüppel-like factor 2 (KLF2) in endothelial cells (ECs) potentially exerts an anti-inflammatory effect. However, the role of extracellular vesicles (EVs) from KLF2-overexpressing ECs (KLF2-EVs) in DCM remains unclear. METHODS AND RESULTS EVs were separated from the supernatant of KLF2-overexpressing ECs by gradient centrifugation. Mice were repeatedly administered low-dose doxorubicin (DOX) and then received KLF2-EVs through an intravenous injection. Treatment with KLF2-EVs prevented doxorubicin-induced left ventricular dysfunction and reduced the recruitment of Ly6high Mo/Mø in the myocardium. We used flow cytometry to detect Ly6high monocytes in bone marrow and spleen tissues and to elucidate the mechanisms underlying this beneficial effect. KLF2-EVs increased the retention of Ly6Chigh monocytes in the bone marrow but not in the spleen tissue. KLF2-EVs also significantly downregulated C-C chemokine receptor 2 (CCR2) protein expression in cells from the bone marrow. CONCLUSIONS EVs derived from KLF2-overexpressing ECs reduced cardiac inflammation and ameliorated left ventricular dysfunction in DCM mice by targeting the CCR2 protein to inhibit Ly6Chigh monocyte mobilization from the bone marrow.
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Affiliation(s)
- Wenfeng Zhang
- Department of Cardiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, China
| | - Ziwei Chen
- Department of Cardiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Shuaihua Qiao
- Department of Cardiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Siyuan Chen
- Department of Cardiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, China
| | - Hongyan Zheng
- Department of Cardiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Xuan Wei
- Department of Cardiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China
| | - Qiaoling Li
- Department of Cardiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China.
| | - Biao Xu
- Department of Cardiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, China. .,Department of Cardiology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China.
| | - Wei Huang
- Department of Cardiology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, China.
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50
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Kang IS, Kwon K. Potential application of biomimetic exosomes in cardiovascular disease: focused on ischemic heart disease. BMB Rep 2022. [PMID: 34903320 PMCID: PMC8810547 DOI: 10.5483/bmbrep.2022.55.1.161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Cardiovascular disease, especially ischemic heart disease, is a major cause of mortality worldwide. Cardiac repair is one of the most promising strategies to address advanced cardiovascular diseases. Despite moderate improvement in heart function via stem cell therapy, there is no evidence of significant improvement in mortality and morbidity beyond standard therapy. The most salutary effect of stem cell therapy are attributed to the paracrine effects and the stem cell-derived exosomes are known as a major contributor. Hence, exosomes are emerging as a promising therapeutic agent and potent biomarkers of cardiovascular disease. Furthermore, they play a role as cellular cargo and facilitate intercellular communication. However, the clinical use of exosomes is hindered by the absence of a standard operating procedures for exosome isolation and characterization, problems related to yield, and heterogeneity. In addition, the successful clinical application of exosomes requires strategies to optimize cargo, improve targeted delivery, and reduce the elimination of exosomes. In this review, we discuss the basic concept of exosomes and stem cell-derived exosomes in cardiovascular disease, and introduce current efforts to overcome the limitations and maximize the benefit of exosomes including engineered biomimetic exosomes.
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Affiliation(s)
- In Sook Kang
- Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul 07804, Korea
| | - Kihwan Kwon
- Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul 07804, Korea
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