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Song R, Zhang L. MicroRNAs and therapeutic potentials in acute and chronic cardiac disease. Drug Discov Today 2024; 29:104179. [PMID: 39276921 DOI: 10.1016/j.drudis.2024.104179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/23/2024] [Accepted: 09/10/2024] [Indexed: 09/17/2024]
Abstract
microRNAs (miRNAs) are small regulatory RNAs implicated in various cardiac disorders. In this review, the role of miRNAs is discussed in relation to acute myocardial infarction and chronic heart failure. In both settings, miRNAs are altered, contributing to injury and adverse remodeling. Notably, miRNA profiles differ between acute ischemic injury and progressive heart failure. Owing to miRNA variabilities between disease stages and delivery difficulties, translation of animal studies to the clinic remains challenging. The identification of distinct miRNA signatures could lead to the development of miRNA therapies tailored to different disease stages. Here, we summarize the current understanding of miRNAs in acute and chronic cardiac diseases, identify knowledge gaps and discuss progress in developing miRNA-based treatment strategies.
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Affiliation(s)
- Rui Song
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
| | - Lubo Zhang
- Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA, USA.
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2
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Lu M, Xu Z, Xu F, Yin C, Guo H, Cheng B. Mechanical network motifs as targets for mechanomedicine. Drug Discov Today 2024; 29:104145. [PMID: 39182599 DOI: 10.1016/j.drudis.2024.104145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 07/26/2024] [Accepted: 08/20/2024] [Indexed: 08/27/2024]
Abstract
The identification and analysis of network motifs has been widely used in the functional analysis of signaling components, disease discovery and other fields. The positive feedback loop (PFL) is a simple but important network motif. The formation of a PFL is regulated by mechanical cues such as substrate stiffness, fiber stretching and cell compression in the cell microenvironment. Here, we propose a new term, 'mechanical PFL', and analyze the mechanisms of mechanical PFLs at molecular, subcellular and cellular scales. More and more therapies are being targeted against mechanosignaling pathways at the experimental and preclinical stages, and exploring mechanical PFLs as potential mechanomedicine targets could be a new direction for disease treatment.
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Affiliation(s)
- Mengnan Lu
- Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710054, PR China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Zhao Xu
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China; The Key Laboratory of Biomedical Information Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Feng Xu
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China; The Key Laboratory of Biomedical Information Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China
| | - Chunyan Yin
- Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710054, PR China.
| | - Hui Guo
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China; Department of Medical Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710054, PR China.
| | - Bo Cheng
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China; The Key Laboratory of Biomedical Information Engineering, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China.
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3
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Bakhashab S, Barber R, O’Neill J, Arden C, Weaver JU. Overexpression of miR-199b-5p in Colony Forming Unit-Hill's Colonies Positively Mediates the Inflammatory Response in Subclinical Cardiovascular Disease Model: Metformin Therapy Attenuates Its Expression. Int J Mol Sci 2024; 25:8087. [PMID: 39125657 PMCID: PMC11311364 DOI: 10.3390/ijms25158087] [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: 06/25/2024] [Revised: 07/20/2024] [Accepted: 07/21/2024] [Indexed: 08/12/2024] Open
Abstract
Well-controlled type 1 diabetes (T1DM) is characterized by inflammation and endothelial dysfunction, thus constituting a suitable model of subclinical cardiovascular disease (CVD). miR-199b-5p overexpression in murine CVD has shown proatherosclerotic effects. We hypothesized that miR-199b-5p would be overexpressed in subclinical CVD yet downregulated following metformin therapy. Inflammatory and vascular markers were measured in 29 individuals with T1DM and 20 matched healthy controls (HCs). miR-199b-5p expression in CFU-Hill's colonies was analyzed from each study group, and correlations with inflammatory/vascular health indices were evaluated. Significant upregulation of miR-199b-5p was observed in T1DM, which was significantly downregulated by metformin. miR-199b-5p correlated positively with vascular endothelial growth factor-D and c-reactive protein (CRP: nonsignificant). ROC analysis determined miR-199b-5p to define subclinical CVD by discriminating between HCs and T1DM individuals. ROC analyses of HbA1c and CRP showed that the upregulation of miR-199b-5p in T1DM individuals defined subclinical CVD at HbA1c > 44.25 mmol and CRP > 4.35 × 106 pg/mL. Ingenuity pathway analysis predicted miR-199b-5p to inhibit the target genes SIRT1, ETS1, and JAG1. Metformin was predicted to downregulate miR-199b-5p via NFATC2 and STAT3 and reverse its downstream effects. This study validated the antiangiogenic properties of miR-199b-5p and substantiated miR-199b-5p overexpression as a biomarker of subclinical CVD. The downregulation of miR-199b-5p by metformin confirmed its cardio-protective effect.
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Affiliation(s)
- Sherin Bakhashab
- Biochemistry Department, King Abdulaziz University, P.O. Box 80218, Jeddah 21589, Saudi Arabia;
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK (J.O.)
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia
| | - Rosie Barber
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK (J.O.)
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
| | - Josie O’Neill
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK (J.O.)
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
| | - Catherine Arden
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK;
| | - Jolanta U. Weaver
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK (J.O.)
- Department of Diabetes, Queen Elizabeth Hospital, Gateshead, Newcastle upon Tyne NE9 6SH, UK
- Vascular Biology and Medicine Theme, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
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Vancheri C, Quatrana A, Morini E, Mariotti C, Mongelli A, Fichera M, Rufini A, Condò I, Testi R, Novelli G, Malisan F, Amati F. An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease. Hum Genomics 2024; 18:50. [PMID: 38778374 PMCID: PMC11110315 DOI: 10.1186/s40246-024-00602-y] [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: 10/11/2023] [Accepted: 03/26/2024] [Indexed: 05/25/2024] Open
Abstract
Friedreich ataxia (FRDA) is a life-threatening hereditary ataxia; its incidence is 1:50,000 individuals in the Caucasian population. A unique therapeutic drug for FRDA, the antioxidant Omaveloxolone, has been recently approved by the US Food and Drug Administration (FDA). FRDA is a multi-systemic neurodegenerative disease; in addition to a progressive neurodegeneration, FRDA is characterized by hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. Cardiomyopathy is the predominant cause of premature death. The onset of FRDA typically occurs between the ages of 5 and 15. Given the complexity and heterogeneity of clinical features and the variability of their onset, the identification of biomarkers capable of assessing disease progression and monitoring the efficacy of treatments is essential to facilitate decision making in clinical practice. We conducted an RNA-seq analysis in peripheral blood mononuclear cells from FRDA patients and healthy donors, identifying a signature of small non-coding RNAs (sncRNAs) capable of distinguishing healthy individuals from the majority of FRDA patients. Among the differentially expressed sncRNAs, microRNAs are a class of small non-coding endogenous RNAs that regulate posttranscriptional silencing of target genes. In FRDA plasma samples, hsa-miR-148a-3p resulted significantly upregulated. The analysis of the Receiver Operating Characteristic (ROC) curve, combining the circulating expression levels of hsa-miR-148a-3p and hsa-miR-223-3p (previously identified by our group), revealed an Area Under the Curve (AUC) of 0.86 (95%, Confidence Interval 0.77-0.95; p-value < 0.0001). An in silico prediction analysis indicated that the IL6ST gene, an interesting marker of neuroinflammation in FRDA, is a common target gene of both miRNAs. Our findings support the evaluation of combined expression levels of different circulating miRNAs as potent epi-biomarkers in FRDA. Moreover, we found hsa-miR-148a-3p significantly over-expressed in Intermediate and Late-Onset Friedreich Ataxia patients' group (IOG and LOG, respectively) compared to healthy individuals, indicating it as a putative prognostic biomarker in this pathology.
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Affiliation(s)
- Chiara Vancheri
- Department of Biomedicine and Prevention, Genetics Unit, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
| | - Andrea Quatrana
- Department of Biomedicine and Prevention, Laboratory of Signal Transduction, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
- Muscular and Neurodegenerative Diseases Laboratory, Bambino Gesù, Children's Hospital, IRCCS, Rome, Italy
| | - Elena Morini
- Department of Biomedicine and Prevention, Genetics Unit, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
| | - Caterina Mariotti
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, 20133, Italy
| | - Alessia Mongelli
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, 20133, Italy
| | - Mario Fichera
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, 20133, Italy
| | - Alessandra Rufini
- Department of Biomedicine and Prevention, Laboratory of Signal Transduction, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
- Saint Camillus International University of Health and Medical Sciences, Rome, 00131, Italy
| | - Ivano Condò
- Department of Biomedicine and Prevention, Laboratory of Signal Transduction, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
| | - Roberto Testi
- Department of Biomedicine and Prevention, Laboratory of Signal Transduction, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, Genetics Unit, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy
- Neuromed Institute, IRCCS, Pozzilli, 86077, Italy
- Department of Pharmacology, School of Medicine, University of Nevada, Reno, NV, 89557, USA
| | - Florence Malisan
- Department of Biomedicine and Prevention, Laboratory of Signal Transduction, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy.
| | - Francesca Amati
- Department of Biomedicine and Prevention, Genetics Unit, Tor Vergata University of Rome, Via Montpellier 1, Rome, 00133, Italy.
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Nappi F. Non-Coding RNA-Targeted Therapy: A State-of-the-Art Review. Int J Mol Sci 2024; 25:3630. [PMID: 38612441 PMCID: PMC11011542 DOI: 10.3390/ijms25073630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/11/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
The use of non-coding RNAs (ncRNAs) as drug targets is being researched due to their discovery and their role in disease. Targeting ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), is an attractive approach for treating various diseases, such as cardiovascular disease and cancer. This seminar discusses the current status of ncRNAs as therapeutic targets in different pathological conditions. Regarding miRNA-based drugs, this approach has made significant progress in preclinical and clinical testing for cardiovascular diseases, where the limitations of conventional pharmacotherapy are evident. The challenges of miRNA-based drugs, including specificity, delivery, and tolerability, will be discussed. New approaches to improve their success will be explored. Furthermore, it extensively discusses the potential development of targeted therapies for cardiovascular disease. Finally, this document reports on the recent advances in identifying and characterizing microRNAs, manipulating them, and translating them into clinical applications. It also addresses the challenges and perspectives towards clinical application.
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Affiliation(s)
- Francesco Nappi
- Department of Cardiac Surgery, Centre Cardiologique du Nord, 93200 Saint-Denis, France
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Nappi F, Avtaar Singh SS, Jitendra V, Alzamil A, Schoell T. The Roles of microRNAs in the Cardiovascular System. Int J Mol Sci 2023; 24:14277. [PMID: 37762578 PMCID: PMC10531750 DOI: 10.3390/ijms241814277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/14/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
The discovery of miRNAs and their role in disease represent a significant breakthrough that has stimulated and propelled research on miRNAs as targets for diagnosis and therapy. Cardiovascular disease is an area where the restrictions of early diagnosis and conventional pharmacotherapy are evident and deserve attention. Therefore, miRNA-based drugs have significant potential for development. Research and its application can make considerable progress, as seen in preclinical and clinical trials. The use of miRNAs is still experimental but has a promising role in diagnosing and predicting a variety of acute coronary syndrome presentations. Its use, either alone or in combination with currently available biomarkers, might be adopted soon, particularly if there is diagnostic ambiguity. In this review, we examine the current understanding of miRNAs as possible targets for diagnosis and treatment in the cardiovascular system. We report on recent advances in recognising and characterising miRNAs with a focus on clinical translation. The latest challenges and perspectives towards clinical application are discussed.
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Affiliation(s)
- Francesco Nappi
- Department of Cardiac Surgery, Centre Cardiologique du Nord, 93200 Saint-Denis, France; (A.A.); (T.S.)
| | | | - Vikram Jitendra
- Department of Cardiothoracic Surgery, Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK;
| | - Almothana Alzamil
- Department of Cardiac Surgery, Centre Cardiologique du Nord, 93200 Saint-Denis, France; (A.A.); (T.S.)
| | - Thibaut Schoell
- Department of Cardiac Surgery, Centre Cardiologique du Nord, 93200 Saint-Denis, France; (A.A.); (T.S.)
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Juni RP, Kocken JMM, Abreu RC, Ottaviani L, Davalan T, Duygu B, Poels EM, Vasilevich A, Hegenbarth JC, Appari M, Bitsch N, Olieslagers S, Schrijvers DM, Stoll M, Heineke J, de Boer J, de Windt LJ, da Costa Martins PA. MicroRNA-216a is essential for cardiac angiogenesis. Mol Ther 2023; 31:1807-1828. [PMID: 37073128 PMCID: PMC10277893 DOI: 10.1016/j.ymthe.2023.04.007] [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] [Received: 02/06/2021] [Revised: 03/18/2023] [Accepted: 04/12/2023] [Indexed: 04/20/2023] Open
Abstract
While it is experimentally supported that impaired myocardial vascularization contributes to a mismatch between myocardial oxygen demand and supply, a mechanistic basis for disruption of coordinated tissue growth and angiogenesis in heart failure remains poorly understood. Silencing strategies that impair microRNA biogenesis have firmly implicated microRNAs in the regulation of angiogenesis, and individual microRNAs prove to be crucial in developmental or tumor angiogenesis. A high-throughput functional screening for the analysis of a whole-genome microRNA silencing library with regard to their phenotypic effect on endothelial cell proliferation as a key parameter, revealed several anti- and pro-proliferative microRNAs. Among those was miR-216a, a pro-angiogenic microRNA which is enriched in cardiac microvascular endothelial cells and reduced in expression under cardiac stress conditions. miR-216a null mice display dramatic cardiac phenotypes related to impaired myocardial vascularization and unbalanced autophagy and inflammation, supporting a model where microRNA regulation of microvascularization impacts the cardiac response to stress.
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Affiliation(s)
- Rio P Juni
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands; Department of Physiology, Amsterdam University Medical Centers, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands
| | - Jordy M M Kocken
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Ricardo C Abreu
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands; Biomaterials and Stem Cell Based Therapeutics Group, CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC, Biotech Parque Tecnológico de Cantanhede, 3060-197 Coimbra, Portugal
| | - Lara Ottaviani
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Tim Davalan
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Burcu Duygu
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Ella M Poels
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Aliaksei Vasilevich
- Department of Biomedical Engineering and Institute for Complex Molecular Systems, University of Eindhoven, Eindhoven, the Netherlands
| | - Jana C Hegenbarth
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Mahesh Appari
- Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU United Kingdom
| | - Nicole Bitsch
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Serve Olieslagers
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Dorien M Schrijvers
- Laboratory of Physiopharmacology, University of Antwerp, 2610 Wilrijk, Belgium
| | - Monika Stoll
- Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, 48149 Münster, Germany; Department of Biochemistry, CARIM School for Cardiovascular Diseases, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Joerg Heineke
- Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; DZHK, Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany
| | - Jan de Boer
- Department of Biomedical Engineering and Institute for Complex Molecular Systems, University of Eindhoven, Eindhoven, the Netherlands
| | - Leon J de Windt
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands
| | - Paula A da Costa Martins
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands; Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal.
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Gholipour A, Zahedmehr A, Shakerian F, Irani S, Oveisee M, Mowla SJ, Malakootian M. Significance of microRNA-targeted ErbB signaling pathway genes in cardiomyocyte differentiation. Mol Cell Probes 2023; 69:101912. [PMID: 37019292 DOI: 10.1016/j.mcp.2023.101912] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 03/31/2023] [Accepted: 03/31/2023] [Indexed: 04/07/2023]
Abstract
OBJECTIVE(S) Cardiomyocyte differentiation is a complex process that follows the progression of gene expression alterations. The ErbB signaling pathway is necessary for various stages of cardiac development. We aimed to identify potential microRNAs targeting the ErbB signaling pathway genes by in silico approaches. METHODS Small RNA-sequencing data were obtained from GSE108021 for cardiomyocyte differentiation. Differentially expressed miRNAs were acquired via the DESeq2 package. Signaling pathways and gene ontology processes for the identified miRNAs were determined and the targeted genes of those miRNAs affecting the ErbB signaling pathway were determined. RESULTS Results revealed highly differentially expressed miRNAs were common between the differentiation stages and they targeted the genes involved in the ErbB signaling pathway as follows: let-7g-5p targets both CDKN1A and NRAS, while let-7c-5p and let-7d-5p hit CDKN1A and NRAS exclusively. let-7 family members targeted MAPK8 and ABL2. GSK3B was targeted by miR-199a-5p and miR-214-3p, and ERBB4 was targeted by miR-199b-3p and miR-653-5p. miR-214-3p, miR-199b-3p, miR-1277-5p, miR-21-5p, and miR-21-3p targeted CBL, mTOR, Jun, JNKK, and GRB1, respectively. MAPK8 was targeted by miR-214-3p, and ABL2 was targeted by miR-125b-5p and miR-1277-5p, too. CONCLUSION We determined miRNAs and their target genes in the ErbB signaling pathway in cardiomyocyte development and consequently heart pathophysiology progression.
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Affiliation(s)
- Akram Gholipour
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran; Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Zahedmehr
- Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Farshad Shakerian
- Cardiovascular Intervention Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran; Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shiva Irani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | | | - Seyed Javad Mowla
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahshid Malakootian
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Shah AM, Giacca M. Small non-coding RNA therapeutics for cardiovascular disease. Eur Heart J 2022; 43:4548-4561. [PMID: 36106499 PMCID: PMC9659475 DOI: 10.1093/eurheartj/ehac463] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 07/29/2022] [Accepted: 08/11/2022] [Indexed: 01/07/2023] Open
Abstract
Novel bio-therapeutic agents that harness the properties of small, non-coding nucleic acids hold great promise for clinical applications. These include antisense oligonucleotides that inhibit messenger RNAs, microRNAs (miRNAs), or long non-coding RNAs; positive effectors of the miRNA pathway (short interfering RNAs and miRNA mimics); or small RNAs that target proteins (i.e. aptamers). These new therapies also offer exciting opportunities for cardiovascular diseases and promise to move the field towards more precise approaches based on disease mechanisms. There have been substantial advances in developing chemical modifications to improve the in vivo pharmacological properties of antisense oligonucleotides and reduce their immunogenicity. Carrier methods (e.g. RNA conjugates, polymers, and lipoplexes) that enhance cellular uptake of RNA therapeutics and stability against degradation by intracellular nucleases are also transforming the field. A number of small non-coding RNA therapies for cardiovascular indications are now approved. Moreover, there is a large pipeline of therapies in clinical development and an even larger list of putative therapies emerging from pre-clinical studies. Progress in this area is reviewed herein along with the hurdles that need to be overcome to allow a broader clinical translation.
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Affiliation(s)
- Ajay M Shah
- King’s College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Mauro Giacca
- King’s College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine and Sciences, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK
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10
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Deboever E, Fistrovich A, Hulme C, Dunckley T. The Omnipresence of DYRK1A in Human Diseases. Int J Mol Sci 2022; 23:ijms23169355. [PMID: 36012629 PMCID: PMC9408930 DOI: 10.3390/ijms23169355] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 01/13/2023] Open
Abstract
The increasing population will challenge healthcare, particularly because the worldwide population has never been older. Therapeutic solutions to age-related disease will be increasingly critical. Kinases are key regulators of human health and represent promising therapeutic targets for novel drug candidates. The dual-specificity tyrosine-regulated kinase (DYRKs) family is of particular interest and, among them, DYRK1A has been implicated ubiquitously in varied human diseases. Herein, we focus on the characteristics of DYRK1A, its regulation and functional role in different human diseases, which leads us to an overview of future research on this protein of promising therapeutic potential.
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Affiliation(s)
- Estelle Deboever
- ASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA
- Correspondence: (E.D.); (T.D.)
| | - Alessandra Fistrovich
- Department of Chemistry and Biochemistry, College of Science, The University of Arizona, Tucson, AZ 85721, USA
- Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA
| | - Christopher Hulme
- Department of Chemistry and Biochemistry, College of Science, The University of Arizona, Tucson, AZ 85721, USA
- Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA
| | - Travis Dunckley
- ASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA
- Correspondence: (E.D.); (T.D.)
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11
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Micro RNA-411 Expression Improves Cardiac Phenotype Following Myocardial Infarction in Mice. JACC Basic Transl Sci 2022; 7:859-875. [PMID: 36317138 PMCID: PMC9617134 DOI: 10.1016/j.jacbts.2022.05.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 05/13/2022] [Accepted: 05/16/2022] [Indexed: 01/23/2023]
Abstract
Induction of endogenous regenerative capacity has emerged as one promising approach to repair damaged hearts following myocardial infarction (MI). Re-expression of factors that are exclusively expressed during embryonic development may reactivate the ability of adult cardiomyocytes to regenerate. Here, we identified miR-411 as a potent inducer of cardiomyocyte proliferation. Overexpression of miR-411 in the heart significantly increased cardiomyocyte proliferation and survival in a model MI. We found that miR-411 enhances the activity of YAP, the main downstream effector of the Hippo pathway, in cardiomyocytes. In conclusion, miR-411 induces cardiomyocyte regeneration and improves cardiac function post-MI likely by modulating the Hippo/YAP pathway.
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Key Words
- CVEC, cardiac vascular endothelial cells
- EdU, 5-ethynyl-2'-deoxyuridine
- Hippo pathway
- LAD, left anterior descending coronary artery
- MI, myocardial infarction
- MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- NFAT, nuclear factor of activated T cells
- NRCF, neonatal rat cardiac fibroblast
- NRCM, neonatal rat cardiomyocytes
- PCR, polymerase chain reaction
- PEI, polyethylenimine
- cTnI, cardiac troponin I
- cardiac remodeling
- heart failure
- miRNA, microRNA
- microRNA-411
- myocardial infarction
- pHH3, phosphohistone H3
- qPCR, quantitative PCR
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12
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Lan C, Chen C, Qu S, Cao N, Luo H, Yu C, Wang N, Xue Y, Xia X, Fan C, Ren H, Yang Y, Jose PA, Xu Z, Wu G, Zeng C. Inhibition of DYRK1A, via histone modification, promotes cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction. EBioMedicine 2022; 82:104139. [PMID: 35810562 PMCID: PMC9278077 DOI: 10.1016/j.ebiom.2022.104139] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 06/16/2022] [Accepted: 06/19/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND While the adult mammalian heart undergoes only modest renewal through cardiomyocyte proliferation, boosting this process is considered a promising therapeutic strategy to repair cardiac injury. This study explored the role and mechanism of dual-specificity tyrosine regulated kinase 1A (DYRK1A) in regulating cardiomyocyte cell cycle activation and cardiac repair after myocardial infarction (MI). METHODS DYRK1A-knockout mice and DYRK1A inhibitors were used to investigate the role of DYRK1A in cardiomyocyte cell cycle activation and cardiac repair following MI. Additionally, we explored the underlying mechanisms by combining genome-wide transcriptomic, epigenomic, and proteomic analyses. FINDINGS In adult mice subjected to MI, both conditional deletion and pharmacological inhibition of DYRK1A induced cardiomyocyte cell cycle activation and cardiac repair with improved cardiac function. Combining genome-wide transcriptomic and epigenomic analyses revealed that DYRK1A knockdown resulted in robust cardiomyocyte cell cycle activation (shown by the enhanced expression of many genes governing cell proliferation) associated with increased deposition of trimethylated histone 3 Lys4 (H3K4me3) and acetylated histone 3 Lys27 (H3K27ac) on the promoter regions of these genes. Mechanistically, via unbiased mass spectrometry, we discovered that WD repeat-containing protein 82 and lysine acetyltransferase 6A were key mediators in the epigenetic modification of H3K4me3 and H3K27ac and subsequent pro-proliferative transcriptome and cardiomyocyte cell cycle activation. INTERPRETATION Our results reveal a significant role of DYRK1A in cardiac repair and suggest a drug target with translational potential for treating cardiomyopathy. FUNDING This study was supported in part by grants from the National Natural Science Foundation of China (81930008, 82022005, 82070296, 82102834), National Key R&D Program of China (2018YFC1312700), Program of Innovative Research Team by the National Natural Science Foundation (81721001), and National Institutes of Health (5R01DK039308-31, 7R37HL023081-37, 5P01HL074940-11).
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Affiliation(s)
- Cong Lan
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Department of Cardiology, General Hospital of Western Theater Command, Chengdu, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Caiyu Chen
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Shuang Qu
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Nian Cao
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; Department of Cardiology, the Sixth Medical Centre, Chinese PLA General Hospital, Beijing, PR China; Department of Internal Medicine, the 519th Hospital of Chinese PLA, Xichang, PR China
| | - Hao Luo
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Cheng Yu
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Na Wang
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Yuanzheng Xue
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Xuewei Xia
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Chao Fan
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Hongmei Ren
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China
| | - Yongjian Yang
- Department of Cardiology, General Hospital of Western Theater Command, Chengdu, PR China
| | - Pedro A Jose
- Division of Renal Diseases & Hypertension, Department of Medicine and Department of Physiology/Pharmacology, The George Washington University School of Medicine & Health Sciences, Washington DC, United States
| | - Zaicheng Xu
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; Department of Cancer Center, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Gengze Wu
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.
| | - Chunyu Zeng
- Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Cardiovascular Research Center of Chongqing College, Department of Cardiology of Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, PR China.
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13
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Abstract
The discovery of microRNAs and their role in diseases was a breakthrough that inspired research into microRNAs as drug targets. Cardiovascular diseases are an area in which limitations of conventional pharmacotherapy are highly apparent and where microRNA-based drugs have appreciably progressed into preclinical and clinical testing. In this Review, we summarize the current state of microRNAs as therapeutic targets in the cardiovascular system. We report recent advances in the identification and characterization of microRNAs, their manipulation and clinical translation, and discuss challenges and perspectives toward clinical application.
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Affiliation(s)
- Bernhard Laggerbauer
- Institute of Pharmacology and Toxicology, Technical University of Munich (TUM), Munich, Germany
| | - Stefan Engelhardt
- Institute of Pharmacology and Toxicology, Technical University of Munich (TUM), Munich, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
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14
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Non-Coding RNAs in the Therapeutic Landscape of Pathological Cardiac Hypertrophy. Cells 2022; 11:cells11111805. [PMID: 35681500 PMCID: PMC9180404 DOI: 10.3390/cells11111805] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/26/2022] [Accepted: 05/26/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases are a major health problem, and long-term survival for people diagnosed with heart failure is, still, unrealistic. Pathological cardiac hypertrophy largely contributes to morbidity and mortality, as effective therapeutic approaches are lacking. Non-coding RNAs (ncRNAs) arise as active regulators of the signaling pathways and mechanisms that govern this pathology, and their therapeutic potential has received great attention in the last decades. Preclinical studies in large animal models have been successful in ameliorating cardiac hypertrophy, and an antisense drug for the treatment of heart failure has, already, entered clinical trials. In this review, we provide an overview of the molecular mechanisms underlying cardiac hypertrophy, the involvement of ncRNAs, and the current therapeutic landscape of oligonucleotides targeting these regulators. Strategies to improve the delivery of such therapeutics and overcome the actual challenges are, also, defined and discussed. With the fast advance in the improvement of oligonucleotide drug delivery, the inclusion of ncRNAs-targeting therapies for cardiac hypertrophy seems, increasingly, a closer reality.
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15
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Kang X, Jiao Y, Zhou Y, Meng C, Zhou X, Song L, Jiao X, Pan Z. MicroRNA-5112 Targets IKKγ to Dampen the Inflammatory Response and Improve Clinical Symptoms in Both Bacterial Infection and DSS-Induced Colitis. Front Immunol 2022; 13:779770. [PMID: 35222370 PMCID: PMC8866336 DOI: 10.3389/fimmu.2022.779770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 01/20/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammation is a double-edged sword that can be induced by various PAMPs, resulting in the control of infection by invading pathogens or injuries. The inflammatory response requires strict and precise control and regulation. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression via translational inhibition or mRNA degradation. However, the role of miRNAs in inflammation induced by flagellin (ligand of TLR5) has yet to be fully determined. In this study, we identified differentially expressed miRNAs in murine bone marrow-derived dendritic cells (BMDCs) between flagellin treatment and medium alone using miRNA microarray. We found that flagellin stimulation downregulated miR-5112 expression in BMDCs and spleen DCs in vitro and in vivo. The overexpression of miR-5112 decreased inflammatory cytokine production, accompanied by a reduction of IKKγ in flagellin-stimulated BMDCs. We demonstrated that miR-5112 could directly target IKKγ to inhibit inflammatory cytokine production. Furthermore, miR-5112 inhibited the inflammatory response induced by flagellin or Salmonella infection in vivo. Interestingly, miR-5112 could also dampen the inflammatory response and alleviate dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice. These results suggest that miR-5112 could be a novel therapeutic target for both bacterial infection and DSS-induced colitis model.
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Affiliation(s)
- Xilong Kang
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Yang Jiao
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Yingying Zhou
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Chuang Meng
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Xiaohui Zhou
- Pathobiology and Veterinary Science, College of Agriculture, Health and Natural Resources, University of Connecticut, Storrs, CT, United States
| | - Li Song
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Xinan Jiao
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
| | - Zhiming Pan
- Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou, China.,Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of Agriculture of China (MOA), Yangzhou University, Yangzhou, China.,Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education, Yangzhou University, Yangzhou, China
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16
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Lin H, Wan N. Circular RNA has Circ 001372-Reduced Inflammation in Ovalbumin-Induced Asthma Through Sirt1/NFAT5 Signaling Pathway by miRNA-128-3p. Mol Biotechnol 2022; 64:1034-1044. [PMID: 35353360 DOI: 10.1007/s12033-022-00480-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 03/14/2022] [Indexed: 02/07/2023]
Abstract
In this study, we sought to investigate the prospective role of circ 001372 in modifying inflammation in ovalbumin-induced asthma. In the vivo model of asthma, the serum of circ 001372 was reduced. Down-regulation of circ 001372 increased inflammation reaction (TNF-α, IL-1β, IL-6, and IL-18) and induced COX-2 and iNOS protein expression in vitro model through activation of NFAT5 and suppression of Sirt1. Up-regulation of circ 001372 decreased inflammation reaction (TNF-α, IL-1β, IL-6, and IL-18) in vitro model through inactivation of NFAT5 and induction of Sirt1 by miRNA-128-3p. The miRNA-128-3p lowered the effects of circ 001372 on inflammation in vitro model. The Sirt1 inhibitor reduced the effects of circ 001372 on inflammation in vitro model. Our results revealed the serum of circ 001372 against inflammation in ovalbumin-induced asthma through Sirt1/NFAT5 by miRNA-128-3p.
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Affiliation(s)
- Hongrui Lin
- Department of Pediatrics, Beijing JiShuiTan Hospital, No. 68 Huinanbei Road, XinJieKou East Street, XiCheng District, Beijing, 100035, China
| | - Naijun Wan
- Department of Pediatrics, Beijing JiShuiTan Hospital, No. 68 Huinanbei Road, XinJieKou East Street, XiCheng District, Beijing, 100035, China.
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17
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New insights into the roles for DYRK family in mammalian development and congenital diseases. Genes Dis 2022. [DOI: 10.1016/j.gendis.2021.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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18
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Atas-Ozcan H, Brault V, Duchon A, Herault Y. Dyrk1a from Gene Function in Development and Physiology to Dosage Correction across Life Span in Down Syndrome. Genes (Basel) 2021; 12:1833. [PMID: 34828439 PMCID: PMC8624927 DOI: 10.3390/genes12111833] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 01/12/2023] Open
Abstract
Down syndrome is the main cause of intellectual disabilities with a large set of comorbidities from developmental origins but also that appeared across life span. Investigation of the genetic overdosage found in Down syndrome, due to the trisomy of human chromosome 21, has pointed to one main driver gene, the Dual-specificity tyrosine-regulated kinase 1A (Dyrk1a). Dyrk1a is a murine homolog of the drosophila minibrain gene. It has been found to be involved in many biological processes during development and in adulthood. Further analysis showed its haploinsufficiency in mental retardation disease 7 and its involvement in Alzheimer's disease. DYRK1A plays a role in major developmental steps of brain development, controlling the proliferation of neural progenitors, the migration of neurons, their dendritogenesis and the function of the synapse. Several strategies targeting the overdosage of DYRK1A in DS with specific kinase inhibitors have showed promising evidence that DS cognitive conditions can be alleviated. Nevertheless, providing conditions for proper temporal treatment and to tackle the neurodevelopmental and the neurodegenerative aspects of DS across life span is still an open question.
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Affiliation(s)
- Helin Atas-Ozcan
- Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (H.A.-O.); (V.B.); (A.D.)
| | - Véronique Brault
- Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (H.A.-O.); (V.B.); (A.D.)
| | - Arnaud Duchon
- Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (H.A.-O.); (V.B.); (A.D.)
| | - Yann Herault
- Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France; (H.A.-O.); (V.B.); (A.D.)
- Université de Strasbourg, CNRS, INSERM, Celphedia, Phenomin-Institut Clinique de la Souris (ICS), 1 rue Laurent Fries, 67404 Illkirch Graffenstaden, France
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19
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Akhavan S, Tutunchi S, Malmir A, Ajorlou P, Jalili A, Panahi G. Molecular study of the proliferation process of beta cells derived from pluripotent stem cells. Mol Biol Rep 2021; 49:1429-1436. [PMID: 34734370 DOI: 10.1007/s11033-021-06892-y] [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: 07/11/2021] [Accepted: 10/28/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Diabetes mellitus (DM) is a chronic metabolic disorder, increasing in the number of patients and poses a severe threat to human health. Significant advances have been made in DM treatment; the most important of which is differentiation and proliferation of beta cells from IPSCs. METHODS Data were collected from PUBMED at various time points up to the academic year of 2020. The related keywords are listed as follows: "Induced pluripotent stem cell", "Proliferation", "Growth factor", "Small molecule", "cardiotoxicity" and "Scaffold." RESULT The use of growth factors along with small molecules can be a good strategy for beta-cell proliferation. Also, proliferation of beta cells on nanofibers scaffolds can create a similar in vivo environment, that leads to increased function of beta-cell. Some transcription factors that cause beta cells proliferation play an important role in inflammation; so, it is essential to monitor them to prevent inflammation. CONCLUSION Finally, the simultaneous use of growth factors, micronutrients and scaffolds can be an excellent strategy to increase the proliferation and function of beta cells derived from IPSCs.
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Affiliation(s)
- Saeedeh Akhavan
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University (IAU), Tehran, Iran
| | - Sara Tutunchi
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ali Malmir
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Parisa Ajorlou
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Arsalan Jalili
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran
| | - Ghodratollah Panahi
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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20
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Ragusa R, Di Molfetta A, Del Turco S, Cabiati M, Del Ry S, Basta G, Mercatanti A, Pitto L, Amodeo A, Trivella MG, Rizzo M, Caselli C. Epigenetic Regulation of Cardiac Troponin Genes in Pediatric Patients with Heart Failure Supported by Ventricular Assist Device. Biomedicines 2021; 9:biomedicines9101409. [PMID: 34680526 PMCID: PMC8533380 DOI: 10.3390/biomedicines9101409] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 09/30/2021] [Accepted: 10/03/2021] [Indexed: 11/16/2022] Open
Abstract
Ventricular Assist Device (VAD) therapy is considered as a part of standard care for end-stage Heart Failure (HF) children unresponsive to medical management, but the potential role of miRNAs in response to VAD therapy on molecular pathways underlying LV remodeling and cardiac function in HF is unknown. The aims of this study were to evaluate the effects of VAD on miRNA expression profile in cardiac tissue obtained from HF children, to determine the putative miRNA targets by an in-silico analysis as well as to verify the changes of predicated miRNA target in the same cardiac samples. The regulatory role of selected miRNAs on predicted targets was evaluated by a dedicated in vitro study. miRNA profile was determined in cardiac samples obtained from 13 HF children [median: 29 months; 19 LVEF%; 9 Kg] by NGS before VAD implant (pre-VAD) and at the moment of heart transplant (Post-VAD). Only hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-1246 were differentially expressed at post-VAD when compared to pre-VAD, and validated by real-time PCR. Putative targets of the selected miRNAs were involved in regulation of sarcomere genes, such as cardiac troponin (cTns) complex. The expression levels of fetal ad adult isoforms of cTns resulted significantly higher after VAD in cardiac tissue of HF pediatric patients when compared with HF adults. An in vitro study confirmed a down-regulatory effect of hsa-miR-19a-3p on cTnC expression. The effect of VAD on sarcomere organization through cTn isoform expression may be epigenetically regulated, suggesting for miRNAs a potential role as therapeutic targets to improve heart function in HF pediatric patients.
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Affiliation(s)
- Rosetta Ragusa
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
- Scuola Superiore Sant’Anna, 56127 Pisa, Italy
| | - Arianna Di Molfetta
- Departement of Cardiothoracic Surgery, Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy; (A.D.M.); (A.A.)
| | - Serena Del Turco
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Manuela Cabiati
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Silvia Del Ry
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Giuseppina Basta
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Alberto Mercatanti
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Letizia Pitto
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Antonio Amodeo
- Departement of Cardiothoracic Surgery, Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy; (A.D.M.); (A.A.)
| | - Maria Giovanna Trivella
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Milena Rizzo
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
| | - Chiara Caselli
- Institute of Clinical Physiology, CNR, 56124 Pisa, Italy; (R.R.); (S.D.T.); (M.C.); (S.D.R.); (G.B.); (A.M.); (L.P.); (M.G.T.); (M.R.)
- Fondazione Toscana Gabriele Monasterio, 56124 Pisa, Italy
- Correspondence: ; Tel.: +39-050-3153551; Fax: +39-050-3152166
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21
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MicroRNAs-The Heart of Post-Myocardial Infarction Remodeling. Diagnostics (Basel) 2021; 11:diagnostics11091675. [PMID: 34574016 PMCID: PMC8469128 DOI: 10.3390/diagnostics11091675] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 09/02/2021] [Accepted: 09/09/2021] [Indexed: 12/20/2022] Open
Abstract
Myocardial infarction (MI) is one of the most frequent cardiac emergencies, with significant potential for mortality. One of the major challenges of the post-MI healing response is that replacement fibrosis could lead to left ventricular remodeling (LVR) and heart failure (HF). This process involves canonical and non-canonical transforming growth factor-beta (TGF-β) signaling pathways translating into an intricate activation of cardiac fibroblasts and disproportionate collagen synthesis. Accumulating evidence has indicated that microRNAs (miRNAs) significantly contribute to the modulation of these signaling pathways. This review summarizes the recent updates regarding the molecular mechanisms underlying the role of the over 30 miRNAs involved in post-MI LVR. In addition, we compare the contradictory roles of several multifunctional miRNAs and highlight their potential use in pressure overload and ischemia-induced fibrosis. Finally, we discuss their attractive role as prognostic biomarkers for HF, highlighting the most relevant human trials involving these miRNAs.
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22
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Abstract
Genomic instability, the unresolved accumulation of DNA variants, is hypothesized as one of the contributors to the natural aging process. We assessed the frequency of unresolved DNA damage reaching the transcriptome of the murine myocardium during the course of natural aging and in hearts from four distinct mouse models of premature aging with established aging-related cardiac dysfunctions. RNA sequencing and variant calling based on total RNA sequencing was compared between hearts from naturally aging mice, mice with cardiomyocyte-specific deficiency of Ercc1, a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity, Tert-deficient mice with reduced telomere length, and a mouse model of human Hutchinson-Gilford progeria syndrome (HGPS). Our results demonstrate that no enrichment in variants is evident in the naturally aging murine hearts until 2 y of age from the HGPS mouse model or mice with reduced telomere lengths. In contrast, a dramatic accumulation of variants was evident in Ercc1 cardiomyocyte-specific knockout mice with deficient DNA repair machinery, in mice with reduced mitochondrial antioxidant capacity, and in the intestine, liver, and lung of naturally aging mice. Our data demonstrate that genomic instability does not evidently contribute to naturally aging of the mouse heart in contrast to other organs and support the contention that the endogenous DNA repair machinery is remarkably active to maintain genomic integrity in cardiac cells throughout life.
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23
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Marracino L, Fortini F, Bouhamida E, Camponogara F, Severi P, Mazzoni E, Patergnani S, D’Aniello E, Campana R, Pinton P, Martini F, Tognon M, Campo G, Ferrari R, Vieceli Dalla Sega F, Rizzo P. Adding a "Notch" to Cardiovascular Disease Therapeutics: A MicroRNA-Based Approach. Front Cell Dev Biol 2021; 9:695114. [PMID: 34527667 PMCID: PMC8435685 DOI: 10.3389/fcell.2021.695114] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 08/09/2021] [Indexed: 12/18/2022] Open
Abstract
Dysregulation of the Notch pathway is implicated in the pathophysiology of cardiovascular diseases (CVDs), but, as of today, therapies based on the re-establishing the physiological levels of Notch in the heart and vessels are not available. A possible reason is the context-dependent role of Notch in the cardiovascular system, which would require a finely tuned, cell-specific approach. MicroRNAs (miRNAs) are short functional endogenous, non-coding RNA sequences able to regulate gene expression at post-transcriptional levels influencing most, if not all, biological processes. Dysregulation of miRNAs expression is implicated in the molecular mechanisms underlying many CVDs. Notch is regulated and regulates a large number of miRNAs expressed in the cardiovascular system and, thus, targeting these miRNAs could represent an avenue to be explored to target Notch for CVDs. In this Review, we provide an overview of both established and potential, based on evidence in other pathologies, crosstalks between miRNAs and Notch in cellular processes underlying atherosclerosis, myocardial ischemia, heart failure, calcification of aortic valve, and arrhythmias. We also discuss the potential advantages, as well as the challenges, of using miRNAs for a Notch-based approach for the diagnosis and treatment of the most common CVDs.
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Affiliation(s)
- Luisa Marracino
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | | | - Esmaa Bouhamida
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Francesca Camponogara
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Paolo Severi
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Elisa Mazzoni
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Simone Patergnani
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Emanuele D’Aniello
- Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy
| | - Roberta Campana
- Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy
| | - Paolo Pinton
- Maria Cecilia Hospital, GVM Care & Research, Ravenna, Italy
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Fernanda Martini
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Mauro Tognon
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Gianluca Campo
- Maria Cecilia Hospital, GVM Care & Research, Ravenna, Italy
- Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy
| | - Roberto Ferrari
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Maria Cecilia Hospital, GVM Care & Research, Ravenna, Italy
| | | | - Paola Rizzo
- Laboratory for Technologies of Advanced Therapies (LTTA), Department of Translational Medicine, University of Ferrara, Ferrara, Italy
- Maria Cecilia Hospital, GVM Care & Research, Ravenna, Italy
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24
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Alshehri AS, El-Kott AF, El-Kenawy AE, Khalifa HS, AlRamlawy AM. Cadmium chloride induces non-alcoholic fatty liver disease in rats by stimulating miR-34a/SIRT1/FXR/p53 axis. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 784:147182. [PMID: 34088068 DOI: 10.1016/j.scitotenv.2021.147182] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/10/2021] [Accepted: 04/12/2021] [Indexed: 06/12/2023]
Abstract
Cadmium (Cd) is associated with non-alcoholic fatty liver disease (NAFLD). The hepatic activation of p53/miR-43a-induced suppression of SIRT1/FXR axis plays a significant role in the development of NAFLD. In this study, we have investigated CdCl2-induced NAFLD in rats involves activation of miR34a/SIRT1/FXR axis. Adult male rats were divided into 4 groups (n-8/each) as a control, CdCl2 (10 mg/l), CdCl2 + miR-34a antagomir (inhibitor), and CdCl2 + SRT1720 (a SIRT1 activator) for 8 weeks, daily. With no effect on fasting glucose and insulin levels, CdCl2 significantly reduced rats' final body, fat pads, and liver weights, and food intake. Concomitantly, it increased the circulatory levels of liver markers (ALT, AST, and γ-GTT), increased the serum and hepatic levels of total cholesterol and triglycerides coincided with increased hepatic lipid accumulation. Besides, it increased the mRNA and protein levels of SREBP1, SREBP2, FAS, and HMGCOA reductase but reduced mRNA levels of PPARα, CPT1, and CPT2. Interestingly, CdCl2 also increased mRNA levels of miR34 without altering mRNA levels of SIRT1 but with a significant reduction in protein levels of SIRT1. These effects were associated with increased total protein levels of p53 and acetylated protein of p53, and FXR. Of note, suppressing miR-34a with a specific anatomic or activating SIRT1 by SRT1720 completely prevented all these effects and reduced hepatic fat accumulations in the livers of rats. In conclusion, CdCl2 induced NAFLD by increasing the transcription of miR-34a which in turn downregulates SIRT1 at the translational level.
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Affiliation(s)
- Ali S Alshehri
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Attalla F El-Kott
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia; Zoology Department, College of Science, Damanhour University, Damanhour, Egypt.
| | - Ayman E El-Kenawy
- Pathology Department, College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Heba S Khalifa
- Zoology Department, College of Science, Damanhour University, Damanhour, Egypt
| | - Amira M AlRamlawy
- Mansoura Research Centre for Cord Stem Cell (MARC-CSC), Stem cells bank, Children's Hospital, Mansoura University, Mansoura, Egypt
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25
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A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration. Nat Commun 2021; 12:4808. [PMID: 34376683 PMCID: PMC8355162 DOI: 10.1038/s41467-021-25211-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 07/28/2021] [Indexed: 11/09/2022] Open
Abstract
Myocardial regeneration is restricted to early postnatal life, when mammalian cardiomyocytes still retain the ability to proliferate. The molecular cues that induce cell cycle arrest of neonatal cardiomyocytes towards terminally differentiated adult heart muscle cells remain obscure. Here we report that the miR-106b~25 cluster is higher expressed in the early postnatal myocardium and decreases in expression towards adulthood, especially under conditions of overload, and orchestrates the transition of cardiomyocyte hyperplasia towards cell cycle arrest and hypertrophy by virtue of its targetome. In line, gene delivery of miR-106b~25 to the mouse heart provokes cardiomyocyte proliferation by targeting a network of negative cell cycle regulators including E2f5, Cdkn1c, Ccne1 and Wee1. Conversely, gene-targeted miR-106b~25 null mice display spontaneous hypertrophic remodeling and exaggerated remodeling to overload by derepression of the prohypertrophic transcription factors Hand2 and Mef2d. Taking advantage of the regulatory function of miR-106b~25 on cardiomyocyte hyperplasia and hypertrophy, viral gene delivery of miR-106b~25 provokes nearly complete regeneration of the adult myocardium after ischemic injury. Our data demonstrate that exploitation of conserved molecular programs can enhance the regenerative capacity of the injured heart.
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26
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Ionescu RF, Cretoiu SM. MicroRNAs as monitoring markers for right-sided heart failure and congestive hepatopathy. J Med Life 2021; 14:142-147. [PMID: 34104236 PMCID: PMC8169151 DOI: 10.25122/jml-2021-0071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The last decades showed a worrying increase in the evolution of cardiovascular diseases towards different stages of heart failure (HF), as a stigma of the western lifestyle. MicroRNAs (miRNAs), non-coding RNAs, which are approximately 22-nucleotide long, were shown to regulate gene expression at the post-transcriptional level and play a role in the pathogenesis and progression of HF. miRNAs research is of high interest nowadays, as these molecules display mechanisms of action that can influence the course of evolution of common chronic diseases, including HF. The potential of post-transcriptional regulation by miRNAs concerning the diagnosis, management, and therapy for HF represents a new promising approach in the accurate assessment of cardiovascular diseases. This review aims to assess the current knowledge of miRNAs in cardiovascular diseases, especially right-sided heart failure and hepatomegaly. Moreover, attention is focused on their role as potential molecular biomarkers and more promising aspects involving miRNAs as future therapeutic targets in the pathophysiology of HF.
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Affiliation(s)
- Ruxandra Florentina Ionescu
- Department of Cardiology I, Central Military Emergency University Hospital Dr. Carol Davila, Bucharest, Romania
| | - Sanda Maria Cretoiu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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27
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RNA interference therapeutics for cardiac regeneration. Curr Opin Genet Dev 2021; 70:48-53. [PMID: 34098251 DOI: 10.1016/j.gde.2021.05.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/16/2021] [Indexed: 12/14/2022]
Abstract
There is an impelling need to develop new therapeutics for myocardial infarction and heart failure. A novel and exciting therapeutic possibility is to achieve cardiac regeneration through the stimulation of the endogenous capacity of cardiomyocytes to proliferate. Proof-of-concept evidence of microRNA-induced cardiac regeneration is available in both small and large animals using viral vectors. However, a clinically more applicable strategy is the development of lipid-mediated nanotechnologies for the administration of RNA therapeutics as synthetic molecules. The recent success of the Stable Nucleic Acid Lipid Particle (SNALP) platform for the generation of nanosized, efficient and non-inflammatory lipid nanoparticles paves the way to the development of injectable nanoformulations of microRNAs through cardiac catheterisation.
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28
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Alshammari GM, Al-Qahtani WH, AlFaris NA, Alzahrani NS, Alkhateeb MA, Yahya MA. Quercetin prevents cadmium chloride-induced hepatic steatosis and fibrosis by downregulating the transcription of miR-21. Biofactors 2021; 47:489-505. [PMID: 33733575 DOI: 10.1002/biof.1724] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 02/16/2021] [Indexed: 12/12/2022]
Abstract
This study investigated if cadmium chloride (CdCl2 )-induced hepatic steatosis and fibrosis and the protective effect of quercetin (QUR) are mediated modulating the activity of miR-21, a known hepatic lipogenic and fibrotic miRNA. Male rats (n = 8/group) were divided as control, control + QUR (50 mg/kg; orally), CdCl2 (10 moml/L; drinking water), CdCl2 + miR-21 antagomir (inhibitor) (16 mg/kg/first 3 days), and CdCl2 + QUR (50 mg/kg). Treatments were conducted for 20 weeks, daily. All treatments showed no effect on fasting glucose and insulin levels. Administration of either miR-21 or QUR prevented CdCl2 -induced hepatic damage, as well as lipid droplets and collagen deposition. They also reduced serum levels of ALT and AST and decreased serum and hepatic levels of total cholesterol, triglycerides, and low-density lipoproteins in CdCl2 -treated rats. Concomitantly, they reduced hepatic levels of reactive oxygen species, malondialdehyde, interleukin-6, and tumor necrosis factor-α, suppressed the activation of NF-kb P65, and increased hepatic levels of nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione (GSH), and superoxide dismutase (SOD). These effects were associated with reduced expression of SREBP1, TGF-β1, Smad3, and collagen1 A and increased expression of PPARα, CPT1, and smad7. Interestingly, QUR significantly lowered levels of miR-21 and increased the protein levels and activity of Nrf2, as well as levels of GSH and SOD in the livers of both the control and CdCl2 -treated rats. Of note, levels of Nrf2 were negatively correlated with the transcription of miR-21. In conclusion: QUR prevents CdCl2 -induced hepatic steatosis and fibrosis mainly through attenuating its ability to upregulate miR-21, at least, by upregulation of Nrf2.
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Affiliation(s)
- Ghedeir M Alshammari
- Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, Riyadh, Saudi Arabia
| | - Wahidah H Al-Qahtani
- Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, Riyadh, Saudi Arabia
| | - Nora A AlFaris
- Nutrition and Food Science, Department of Physical Sport Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Nadiah S Alzahrani
- Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, Riyadh, Saudi Arabia
| | - Mahmoud A Alkhateeb
- Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
| | - Mohammed Abdo Yahya
- Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, Riyadh, Saudi Arabia
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29
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Wang W, Zheng H. Myocardial Infarction: The Protective Role of MiRNAs in Myocardium Pathology. Front Cardiovasc Med 2021; 8:631817. [PMID: 33748196 PMCID: PMC7973051 DOI: 10.3389/fcvm.2021.631817] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases have been regarded as the leading cause of death around the world, with myocardial infarction (MI) being the most severe form. MI leads to myocardial apoptosis, cardiomyocyte fibrosis, and cardiomyocyte hypertrophy, ultimately leading to heart failure, and death. Micro RNAs (miRNAs) participate in the genesis and progression of myocardial pathology after MI by playing an important regulatory role. This review aims to summarize all available knowledge on the role of miRNAs in the myocardial pathological process after MI to uncover potential major target pathways. In addition, the main therapeutic methods and their latest progress are also reviewed. miRNAs can regulate the main signaling pathways as well as pathological processes. Thus, they have the potential to induce therapeutic effects. Hence, the combination of miRNAs with recently developed exosome nanocomplexes may represent the future direction of therapeutics.
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Affiliation(s)
- Wei Wang
- Graduate School of Bengbu Medical College, Bengbu, China
| | - Hao Zheng
- Department of Cardiovascular Medicine, Zhejiang Provincial People's Hospital, Hangzhou, China
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30
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Li J, Richmond B, Hong T. Cardiac T-Tubule cBIN1-Microdomain, a Diagnostic Marker and Therapeutic Target of Heart Failure. Int J Mol Sci 2021; 22:ijms22052299. [PMID: 33669042 PMCID: PMC7956774 DOI: 10.3390/ijms22052299] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/19/2021] [Accepted: 02/22/2021] [Indexed: 12/23/2022] Open
Abstract
Since its first identification as a cardiac transverse tubule (t-tubule) protein, followed by the cloning of the cardiac isoform responsible for t-tubule membrane microdomain formation, cardiac bridging integrator 1 (cBIN1) and its organized microdomains have emerged as a key mechanism in maintaining normal beat-to-beat heart contraction and relaxation. The abnormal remodeling of cBIN1-microdomains occurs in stressed and diseased cardiomyocytes, contributing to the pathophysiology of heart failure. Due to the homeostatic turnover of t-tubule cBIN1-microdomains via microvesicle release into the peripheral circulation, plasma cBIN1 can be assayed as a liquid biopsy of cardiomyocyte health. A new blood test cBIN1 score (CS) has been developed as a dimensionless inverse index derived from plasma cBIN1 concentration with a diagnostic and prognostic power for clinical outcomes in stable ambulatory patients with heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). Recent evidence further indicates that exogenous cBIN1 introduced by adeno-associated virus 9-based gene therapy can rescue cardiac contraction and relaxation in failing hearts. The therapeutic potential of cBIN1 gene therapy is enormous given its ability to rescue cardiac inotropy and provide lusitropic protection in the meantime. These unprecedented capabilities of cBIN1 gene therapy are shifting the current paradigm of therapy development for heart failure, particularly HFpEF.
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Affiliation(s)
- Jing Li
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA; (J.L.); (B.R.)
| | - Bradley Richmond
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA; (J.L.); (B.R.)
| | - TingTing Hong
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA; (J.L.); (B.R.)
- Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112, USA
- Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT 84112, USA
- Correspondence: ; Tel.: +1-801-581-3090
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31
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Langlo KAR, Silva GJJ, Overrein TS, Adams V, Wisløff U, Dalen H, Rolim N, Hallan SI. Circulating microRNAs May Serve as Biomarkers for Hypertensive Emergency End-Organ Injuries and Address Underlying Pathways in an Animal Model. Front Cardiovasc Med 2021; 7:626699. [PMID: 33644125 PMCID: PMC7906971 DOI: 10.3389/fcvm.2020.626699] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 12/31/2020] [Indexed: 11/20/2022] Open
Abstract
There is an incomplete understanding of the underlying pathophysiology in hypertensive emergencies, where severely elevated blood pressure causes acute end-organ injuries, as opposed to the long-term manifestations of chronic hypertension. Furthermore, current biomarkers are unable to detect early end-organ injuries like hypertensive encephalopathy and renal thrombotic microangiopathy. We hypothesized that circulating microRNAs (c-miRs) could identify acute and chronic complications of severe hypertension, and that combinations of c-miRs could elucidate important pathways involved. We studied the diagnostic accuracy of 145 c-miRs in Dahl salt-sensitive rats fed either a low-salt (N = 20: 0.3% NaCl) or a high-salt (N = 60: 8% NaCl) diet. Subclinical hypertensive encephalopathy and thrombotic microangiopathy were diagnosed by histopathology. In addition, heart failure with preserved ejection fraction was evaluated with echocardiography and N-terminal pro-brain natriuretic peptide; and endothelial dysfunction was studied using acetylcholine-induced aorta ring relaxation. Systolic blood pressure increased severely in animals on a high-salt diet (high-salt 205 ± 20 mm Hg vs. low-salt 152 ± 18 mm Hg, p < 0.001). Partial least squares discriminant analysis revealed 68 c-miRs discriminating between animals with and without hypertensive emergency complications. Twenty-nine c-miRs were strongly associated with hypertensive encephalopathy, 24 c-miRs with thrombotic microangiopathy, 30 c-miRs with heart failure with preserved ejection fraction, and 28 c-miRs with endothelial dysfunction. Hypertensive encephalopathy, thrombotic microangiopathy and heart failure with preserved ejection fraction were associated with deviations in many of the same c-miRs, whereas endothelial dysfunction was associated with a different set of c-miRs. Several of these c-miRs demonstrated fair to good diagnostic accuracy for a composite outcome of hypertensive encephalopathy, thrombotic microangiopathy and heart failure with preserved ejection fraction in receiver-operating-curve analyses (area-under-curve 0.75–0.88). Target prediction revealed an enrichment of genes related to several pathways relevant for cardiovascular disease (e.g., mucin type O-glycan biosynthesis, MAPK, Wnt, Hippo, and TGF-beta signaling). C-miRs could potentially serve as biomarkers of severe hypertensive end-organ injuries and elucidate important pathways involved.
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Affiliation(s)
- Knut Asbjørn Rise Langlo
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Nephrology, Clinic of Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Gustavo Jose Justo Silva
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.,Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Tina Syvertsen Overrein
- Division of Pathology and Medical Genetics, Department of Laboratory Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Volker Adams
- Department of Cardiology, Heart Center Dresden, TU Dresden, Dresden, Germany
| | - Ulrik Wisløff
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.,School of Human Movement & Nutrition Sciences, University of Queensland, Brisbane, QLD, Australia
| | - Håvard Dalen
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.,Clinic of Cardiology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
| | - Natale Rolim
- Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Stein Ivar Hallan
- Department of Nephrology, Clinic of Medicine, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
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32
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Saadat S, Noureddini M, Mahjoubin-Tehran M, Nazemi S, Shojaie L, Aschner M, Maleki B, Abbasi-Kolli M, Rajabi Moghadam H, Alani B, Mirzaei H. Pivotal Role of TGF-β/Smad Signaling in Cardiac Fibrosis: Non-coding RNAs as Effectual Players. Front Cardiovasc Med 2021; 7:588347. [PMID: 33569393 PMCID: PMC7868343 DOI: 10.3389/fcvm.2020.588347] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/15/2020] [Indexed: 12/21/2022] Open
Abstract
Unintended cardiac fibroblast proliferation in many pathophysiological heart conditions, known as cardiac fibrosis, results in pooling of extracellular matrix (ECM) proteins in the heart muscle. Transforming growth factor β (TGF-β) as a pivotal cytokine/growth factor stimulates fibroblasts and hastens ECM production in injured tissues. The TGF-β receptor is a heterodimeric receptor complex on the plasma membrane, made up from TGF-β type I, as well as type II receptors, giving rise to Smad2 and Smad3 transcription factors phosphorylation upon canonical signaling. Phosphorylated Smad2, Smad3, and cytoplasmic Smad4 intercommunicate to transfer the signal to the nucleus, culminating in provoked gene transcription. Additionally, TGF-β receptor complex activation starts up non-canonical signaling that lead to the mitogen-stimulated protein kinase cascade activation, inducing p38, JNK1/2 (c-Jun NH2-terminal kinase 1/2), and ERK1/2 (extracellular signal–regulated kinase 1/2) signaling. TGF-β not only activates fibroblasts and stimulates them to differentiate into myofibroblasts, which produce ECM proteins, but also promotes fibroblast proliferation. Non-coding RNAs (ncRNAs) are important regulators of numerous pathways along with cellular procedures. MicroRNAs and circular long ncRNAs, combined with long ncRNAs, are capable of affecting TGF-β/Smad signaling, leading to cardiac fibrosis. More comprehensive knowledge based on these processes may bring about new diagnostic and therapeutic approaches for different cardiac disorders.
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Affiliation(s)
- Somayeh Saadat
- Physiology Research Centre, Kashan University of Medical Sciences, Kashan, Iran
| | - Mahdi Noureddini
- Physiology Research Centre, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sina Nazemi
- Vascular and Thorax Surgery Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Layla Shojaie
- Department of Medicine, Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Behnaz Maleki
- Physiology Research Centre, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hasan Rajabi Moghadam
- Department of Cardiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Behrang Alani
- Department of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Laham AJ, Saber-Ayad M, El-Awady R. DYRK1A: a down syndrome-related dual protein kinase with a versatile role in tumorigenesis. Cell Mol Life Sci 2021; 78:603-619. [PMID: 32870330 PMCID: PMC11071757 DOI: 10.1007/s00018-020-03626-4] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/22/2020] [Accepted: 08/18/2020] [Indexed: 12/14/2022]
Abstract
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a dual kinase that can phosphorylate its own activation loop on tyrosine residue and phosphorylate its substrates on threonine and serine residues. It is the most studied member of DYRK kinases, because its gene maps to human chromosome 21 within the Down syndrome critical region (DSCR). DYRK1A overexpression was found to be responsible for the phenotypic features observed in Down syndrome such as mental retardation, early onset neurodegenerative, and developmental heart defects. Besides its dual activity in phosphorylation, DYRK1A carries the characteristic of duality in tumorigenesis. Many studies indicate its possible role as a tumor suppressor gene; however, others prove its pro-oncogenic activity. In this review, we will focus on its multifaceted role in tumorigenesis by explaining its participation in some cancer hallmarks pathways such as proliferative signaling, transcription, stress, DNA damage repair, apoptosis, and angiogenesis, and finally, we will discuss targeting DYRK1A as a potential strategy for management of cancer and neurodegenerative disorders.
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Affiliation(s)
- Amina Jamal Laham
- College of Medicine, University of Sharjah, Sharjah, UAE
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE
| | - Maha Saber-Ayad
- College of Medicine, University of Sharjah, Sharjah, UAE.
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE.
| | - Raafat El-Awady
- College of Medicine, University of Sharjah, Sharjah, UAE.
- College of Pharmacy, University of Sharjah, Sharjah, UAE.
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Schimmel K, Stojanović SD, Huang CK, Jung M, Meyer MH, Xiao K, Grote-Levi L, Bär C, Pfanne A, Mitzka S, Just A, Geffers R, Bock K, Kenneweg F, Kleemiß F, Falk CS, Fiedler J, Thum T. Combined high-throughput library screening and next generation RNA sequencing uncover microRNAs controlling human cardiac fibroblast biology. J Mol Cell Cardiol 2021; 150:91-100. [PMID: 33127387 DOI: 10.1016/j.yjmcc.2020.10.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/08/2020] [Accepted: 10/16/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Myocardial fibrosis is a hallmark of the failing heart, contributing to the most common causes of deaths worldwide. Several microRNAs (miRNAs, miRs) controlling cardiac fibrosis were identified in recent years; however, a more global approach to identify miRNAs involved in fibrosis is missing. METHODS AND RESULTS Functional miRNA mimic library screens were applied in human cardiac fibroblasts (HCFs) to identify annotated miRNAs inducing proliferation. In parallel, miRNA deep sequencing was performed after subjecting HCFs to proliferating and resting stimuli, additionally enabling discovery of novel miRNAs. In-depth in vitro analysis confirmed the pro-fibrotic nature of selected, highly conserved miRNAs miR-20a-5p and miR-132-3p. To determine downstream cellular pathways and their role in the fibrotic response, targets of the annotated miRNA candidates were modulated by synthetic siRNA. We here provide evidence that repression of autophagy and detoxification of reactive oxygen species by miR-20a-5p and miR-132-3p explain some of their pro-fibrotic nature on a mechanistic level. CONCLUSION We here identified both miR-20a-5p and miR-132-3p as crucial regulators of fibrotic pathways in an in vitro model of human cardiac fibroblast biology.
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Affiliation(s)
- Katharina Schimmel
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Stevan D Stojanović
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Cheng-Kai Huang
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Mira Jung
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Martin H Meyer
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Ke Xiao
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Lea Grote-Levi
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Christian Bär
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Angelika Pfanne
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Saskia Mitzka
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Annette Just
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Robert Geffers
- Helmholtz Centre for Infection Research, Research Group Genome Analytics, Braunschweig, Germany
| | - Katharina Bock
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Franziska Kenneweg
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Felix Kleemiß
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Christine S Falk
- Transplant Immunology, Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Germany
| | - Jan Fiedler
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany; REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany.
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Epigenetic Regulation of Pulmonary Arterial Hypertension-Induced Vascular and Right Ventricular Remodeling: New Opportunities? Int J Mol Sci 2020; 21:ijms21238901. [PMID: 33255338 PMCID: PMC7727715 DOI: 10.3390/ijms21238901] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 12/11/2022] Open
Abstract
Pulmonary artery hypertension (PAH) is a rare chronic disease with high impact on patients’ quality of life and currently no available cure. PAH is characterized by constant remodeling of the pulmonary artery by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), fibroblasts (FBs) and endothelial cells (ECs). This remodeling eventually leads to increased pressure in the right ventricle (RV) and subsequent right ventricle hypertrophy (RVH) which, when left untreated, progresses into right ventricle failure (RVF). PAH can not only originate from heritable mutations, but also develop as a consequence of congenital heart disease, exposure to drugs or toxins, HIV, connective tissue disease or be idiopathic. While much attention was drawn into investigating and developing therapies related to the most well understood signaling pathways in PAH, in the last decade, a shift towards understanding the epigenetic mechanisms driving the disease occurred. In this review, we reflect on the different epigenetic regulatory factors that are associated with the pathology of RV remodeling, and on their relevance towards a better understanding of the disease and subsequently, the development of new and more efficient therapeutic strategies.
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Yan H, Wang H, Zhu X, Huang J, Li Y, Zhou K, Hua Y, Yan F, Wang DZ, Luo Y. Adeno-associated virus-mediated delivery of anti-miR-199a tough decoys attenuates cardiac hypertrophy by targeting PGC-1alpha. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 23:406-417. [PMID: 33473326 PMCID: PMC7787996 DOI: 10.1016/j.omtn.2020.11.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 11/10/2020] [Indexed: 02/08/2023]
Abstract
MicroRNAs (miRNAs) are important regulators in the process of cardiac hypertrophy and heart failure. Previous studies have shown that miR-199a is upregulated in pressure-overload cardiac hypertrophy and that inhibition of miR-199a attenuates cardiac hypertrophy in vitro. However, the therapeutic role of anti-miR-199a treatment in the cardiac hypertrophy in vivo model is less known. Here, we show an efficient and useful method to treat mouse cardiac hypertrophy and restore cardiac function through injection of adeno-associated virus (AAV)-mediated anti-miR-199a tough decoys (TuDs). RNA-seq transcriptome analysis indicated that genes related to cytoplasmic translation and mitochondrial respiratory chain complex assembly were upregulated in anti-miR-199a-treated recovered hearts. We further validated that PGC-1α is the direct target of miR-199a involved in the therapeutic effect and the regulation of the PGC-1α/ERRα axis and that the downstream pathway of mitochondrial fatty acid oxidation and oxidative phosphorylation constitute the underlying mechanism of the restored mitochondrial structure and function in our anti-miR-199a-treated mice. Our study highlights the important regulatory role of miR-199a in cardiac hypertrophy and the value of the AAV-mediated miRNA delivery system.
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Affiliation(s)
- Hualin Yan
- Department of Medical Ultrasound, Laboratory of Ultrasound Imaging Drug, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hong Wang
- Department of Medical Ultrasound, Laboratory of Ultrasound Imaging Drug, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaoxia Zhu
- Department of Medical Ultrasound, Laboratory of Ultrasound Imaging Drug, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jianbo Huang
- Department of Medical Ultrasound, Laboratory of Ultrasound Imaging Drug, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yifei Li
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China.,Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Kaiyu Zhou
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China.,Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Yimin Hua
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China.,Ministry of Education Key Laboratory of Women and Children's Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Feng Yan
- Department of Medical Ultrasound, Laboratory of Ultrasound Imaging Drug, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Da-Zhi Wang
- Department of Cardiology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Yan Luo
- Department of Medical Ultrasound, Laboratory of Ultrasound Imaging Drug, West China Hospital, Sichuan University, Chengdu 610041, China
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Boni J, Rubio-Perez C, López-Bigas N, Fillat C, de la Luna S. The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities. Cancers (Basel) 2020; 12:cancers12082106. [PMID: 32751160 PMCID: PMC7465136 DOI: 10.3390/cancers12082106] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 07/24/2020] [Accepted: 07/27/2020] [Indexed: 12/15/2022] Open
Abstract
DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs are pleiotropic factors that phosphorylate a broad set of proteins involved in many different cellular processes. These include factors that have been associated with all the hallmarks of cancer, from genomic instability to increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant to tumor onset and progression. In accordance with an involvement of DYRK kinases in the regulation of tumorigenic processes, an increasing number of research studies have been published in recent years showing either alterations of DYRK gene expression in tumor samples and/or providing evidence of DYRK-dependent mechanisms that contribute to tumor initiation and/or progression. In the present article, we will review the current understanding of the role of DYRK family members in cancer initiation and progression, providing an overview of the small molecules that act as DYRK inhibitors and discussing the clinical implications and therapeutic opportunities currently available.
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Affiliation(s)
- Jacopo Boni
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr Aiguader 88, 08003 Barcelona, Spain;
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 28029 Madrid, Spain
| | - Carlota Rubio-Perez
- Cancer Science Programme, Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028 Barcelona, Spain; (C.R.-P.); (N.L.-B.)
| | - Nuria López-Bigas
- Cancer Science Programme, Institute for Research in Biomedicine (IRB), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028 Barcelona, Spain; (C.R.-P.); (N.L.-B.)
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain
| | - Cristina Fillat
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 28029 Madrid, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149-153, 08036 Barcelona, Spain;
| | - Susana de la Luna
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr Aiguader 88, 08003 Barcelona, Spain;
- Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), 28029 Madrid, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain
- Correspondence: ; Tel.: +34-933-160-144
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Santos-Faria J, Gavina C, Rodrigues P, Coelho J, da Costa Martins P, Leite-Moreira A, Falcão-Pires I. MicroRNAs and ventricular remodeling in aortic stenosis. Rev Port Cardiol 2020; 39:377-387. [PMID: 32682570 DOI: 10.1016/j.repc.2019.09.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 07/03/2019] [Accepted: 09/08/2019] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION AND OBJECTIVES Several mechanisms contribute to myocardial hypertrophy and fibrosis in aortic stenosis (AS). MicroRNAs are post-transcriptional modulators of such processes. We hypothesized that their expression in myocardial biopsies from patients with AS could be linked with the degree of left ventricular (LV) hypertrophy and remodeling and to plasma levels of important biomarkers of extracellular matrix turnover. METHODS We performed myocardial biopsies in eleven patients with isolated severe AS undergoing aortic valve replacement. Echocardiographic exams and biomarker quantification were also performed. Five explanted hearts were used as controls for microRNA expression. RESULTS Overexpression of microRNA-101-3p was found in AS, which correlated with higher levels of preoperative valvuloarterial impedance, angiotensin II receptor and angiotensin-converting enzyme, and LV mass regression after surgery. Although not differently expressed in AS compared to controls, both upregulation of miR-4268 and downregulation of microRNA-125-5p were associated with higher LV mass. MicroRNA-125b-5p correlated negatively with LV mass and with relative wall thickness at six-month follow-up. MicroRNA-4268 correlated positively with LV mass regression and was associated with higher plasma angiotensin II receptor levels. CONCLUSIONS MicroRNA-101-3p and microRNA-4268 have potential new roles in the modulation of the hypertrophic response to AS via the renin-angiotensin-aldosterone system and as predictors of reverse remodeling after aortic valve replacement. Our results open new avenues in the understanding of myocardial response to pressure overload and of reverse remodeling after unloading. They also support the possibility of medical therapy to modulate the renin-angiotensin-aldosterone system in hypertrophic hearts.
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Affiliation(s)
| | - Cristina Gavina
- Department of Cardiology, Hospital Pedro Hispano - Unidade de Saúde Local de Matosinhos, Matosinhos, Portugal; Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Porto, Portugal
| | - Patrícia Rodrigues
- Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Porto, Portugal
| | - João Coelho
- Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Porto, Portugal
| | - Paula da Costa Martins
- Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Porto, Portugal; Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Adelino Leite-Moreira
- Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Porto, Portugal; Department of Cardiothoracic Surgery, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Inês Falcão-Pires
- Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, Porto, Portugal
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Peters LJF, Biessen EAL, Hohl M, Weber C, van der Vorst EPC, Santovito D. Small Things Matter: Relevance of MicroRNAs in Cardiovascular Disease. Front Physiol 2020; 11:793. [PMID: 32733281 PMCID: PMC7358539 DOI: 10.3389/fphys.2020.00793] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/15/2020] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are short sequences of non-coding RNA that play an important role in the regulation of gene expression and thereby in many physiological and pathological processes. Furthermore, miRNAs are released in the extracellular space, for example in vesicles, and are detectable in various biological fluids, such as serum, plasma, and urine. Over the last years, it has been shown that miRNAs are crucial in the development of several cardiovascular diseases (CVDs). This review discusses the (patho)physiological implications of miRNAs in CVD, ranging from cardiovascular risk factors (i.e., hypertension, diabetes, dyslipidemia), to atherosclerosis, myocardial infarction, and cardiac remodeling. Moreover, the intriguing possibility of their use as disease-specific diagnostic and prognostic biomarkers for human CVDs will be discussed in detail. Finally, as several approaches have been developed to alter miRNA expression and function (i.e., mimics, antagomirs, and target-site blockers), we will highlight the miRNAs with the most promising therapeutic potential that may represent suitable candidates for therapeutic intervention in future translational studies and ultimately in clinical trials. All in all, this review gives a comprehensive overview of the most relevant miRNAs in CVD and discusses their potential use as biomarkers and even therapeutic targets.
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Affiliation(s)
- Linsey J. F. Peters
- Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany
- Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, Netherlands
- Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany
- German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
| | - Erik A. L. Biessen
- Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany
- Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Mathias Hohl
- Klinik für Innere Medizin III, Universität des Saarlandes, Homburg, Germany
| | - Christian Weber
- German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, Netherlands
- Munich Cluster for Systems Neurology, Munich, Germany
| | - Emiel P. C. van der Vorst
- Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany
- Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, Netherlands
- Interdisciplinary Center for Clinical Research, RWTH Aachen University, Aachen, Germany
- German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Donato Santovito
- German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
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40
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Santos-Faria J, Gavina C, Rodrigues P, Coelho J, da Costa Martins P, Leite-Moreira A, Falcão-Pires I. MicroRNAs and ventricular remodeling in aortic stenosis. REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2020. [DOI: 10.1016/j.repce.2020.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Abstract
While clinical gene therapy celebrates its first successes, with several products already approved for clinical use and several hundreds in the final stages of the clinical approval pipeline, there is not a single gene therapy approach that has worked for the heart. Here, we review the past experience gained in the several cardiac gene therapy clinical trials that had the goal of inducing therapeutic angiogenesis in the ischemic heart and in the attempts at modulating cardiac function in heart failure. Critical assessment of the results so far achieved indicates that the efficiency of cardiac gene delivery remains a major hurdle preventing success but also that improvements need to be sought in establishing more reliable large animal models, choosing more effective therapeutic genes, better designing clinical trials, and more deeply understanding cardiac biology. We also emphasize a few areas of cardiac gene therapy development that hold great promise for the future. In particular, the transition from gene addition studies using protein-coding cDNAs to the modulation of gene expression using small RNA therapeutics and the improvement of precise gene editing now pave the way to applications such as cardiac regeneration after myocardial infarction and gene correction for inherited cardiomyopathies that were unapproachable until a decade ago.
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Affiliation(s)
- Antonio Cannatà
- From the King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, United Kingdom (A.C., H.A., M.G.).,Department of Medical, Surgical and Health Sciences, University of Trieste, Italy (A.C., G.S., M.G.)
| | - Hashim Ali
- From the King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, United Kingdom (A.C., H.A., M.G.).,Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy (H.A., M.G.)
| | - Gianfranco Sinagra
- Department of Medical, Surgical and Health Sciences, University of Trieste, Italy (A.C., G.S., M.G.)
| | - Mauro Giacca
- From the King's College London, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, United Kingdom (A.C., H.A., M.G.).,Department of Medical, Surgical and Health Sciences, University of Trieste, Italy (A.C., G.S., M.G.).,Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy (H.A., M.G.)
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42
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Jan MI, Ali T, Ishtiaq A, Mushtaq I, Murtaza I. Prospective Advances in Non-coding RNAs Investigation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1229:385-426. [PMID: 32285426 DOI: 10.1007/978-981-15-1671-9_24] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Non-coding RNAs (ncRNAs) play significant roles in numerous physiological cellular processes and molecular alterations during pathological conditions including heart diseases, cancer, immunological disorders and neurological diseases. This chapter is focusing on the basis of ncRNA relation with their functions and prospective advances in non-coding RNAs particularly miRNAs investigation in the cardiovascular disease management.The field of ncRNAs therapeutics is a very fascinating and challenging too. Scientists have opportunity to develop more advanced therapeutics as well as diagnostic approaches for cardiovascular conditions. Advanced studies are critically needed to deepen the understanding of the molecular biology, mechanism and modulation of ncRNAs and chemical formulations for managing CVDs.
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Affiliation(s)
- Muhammad Ishtiaq Jan
- Department of Biochemistry, Signal Transduction Laboratory, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Tahir Ali
- Department of Biochemistry, Signal Transduction Laboratory, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Ayesha Ishtiaq
- Department of Biochemistry, Signal Transduction Laboratory, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Iram Mushtaq
- Department of Biochemistry, Signal Transduction Laboratory, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Iram Murtaza
- Department of Biochemistry, Signal Transduction Laboratory, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Duan C, Cao Z, Tang F, Jian Z, Liang C, Liu H, Xiao Y, Liu L, Ma R. miRNA-mRNA crosstalk in myocardial ischemia induced by calcified aortic valve stenosis. Aging (Albany NY) 2020; 11:448-466. [PMID: 30651404 PMCID: PMC6366972 DOI: 10.18632/aging.101751] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 12/27/2018] [Indexed: 12/24/2022]
Abstract
Aortic valve stenosis is the most common cause of morbidity and mortality in valvular heart disease in aged people. Both microRNA (miRNA) and mRNA are potential targets for the diagnosis and therapeutic intervention of myocardial ischemia induced by calcified aortic valve stenosis (CAVS), with unclear mechanisms. Here, 3 gene expression profiles of 47 male participants were applied to generate shared differentially expressed genes (DEGs) with significant major biological functions. Moreover, 20 hub genes were generated by a Weighted Genes Co-Expression Network Analysis (WGCNA) and were cross-linked to miRNA based on miRanda/miRwalk2 databases. Integrated miRNA/mRNA analysis identified several novel miRNAs and targeted genes as diagnostic/prognostic biomarkers or therapeutic targets in CAVS patients. In addition, the clinical data suggested that myocardial hypertrophy and myocardial ischemia in CAVS patients are likely associated with hub genes and the upstream regulatory miRNAs. Together, our data provide evidence that miRNAs and their targeted genes play an important role in the pathogenesis of myocardial hypertrophy and ischemia in patients with CAVS.
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Affiliation(s)
- Chenyang Duan
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing 400042, P. R. China.,Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, P. R. China
| | - Zhezhe Cao
- Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, P. R. China
| | - Fuqin Tang
- Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, P. R. China
| | - Zhao Jian
- Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, P. R. China
| | - Chunshui Liang
- Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, P. R. China
| | - Hong Liu
- Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, P. R. China
| | - Yingbin Xiao
- Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, P. R. China
| | - Liangming Liu
- State Key Laboratory of Trauma, Burns and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing 400042, P. R. China
| | - Ruiyan Ma
- Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, P. R. China
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LaRocca TJ, Seeger T, Prado M, Perea-Gil I, Neofytou E, Mecham BH, Ameen M, Chang ACY, Pandey G, Wu JC, Karakikes I. Pharmacological Silencing of MicroRNA-152 Prevents Pressure Overload-Induced Heart Failure. Circ Heart Fail 2020; 13:e006298. [PMID: 32160771 DOI: 10.1161/circheartfailure.119.006298] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND MicroRNAs are small, noncoding RNAs that play a key role in gene expression. Accumulating evidence suggests that aberrant microRNA expression contributes to the heart failure (HF) phenotype; however, the underlying molecular mechanisms are not well understood. A better understanding of the mechanisms of action of microRNAs could potentially lead to targeted therapies that could halt the progression or even reverse HF. METHODS AND RESULTS We found that microRNA-152 (miR-152) expression was upregulated in the failing human heart and experimental animal models of HF. Transgenic mice with cardiomyocyte-specific miR-152 overexpression developed systolic dysfunction (mean difference, -38.74% [95% CI, -45.73% to -31.74%]; P<0.001) and dilated cardiomyopathy. At the cellular level, miR-152 overexpression perturbed mitochondrial ultrastructure and dysregulated key genes involved in cardiomyocyte metabolism and inflammation. Mechanistically, we identified Glrx5 (glutaredoxin 5), a critical regulator of mitochondrial iron homeostasis and iron-sulfur cluster synthesis, as a direct miR-152 target. Finally, a proof-of-concept of the therapeutic efficacy of targeting miR-152 in vivo was obtained by utilizing a locked nucleic acid-based inhibitor of miR-152 (LNA 152) in a murine model of HF subjected to transverse aortic constriction. We demonstrated that animals treated with LNA-152 (n=10) showed preservation of systolic function when compared with locked nucleic acid-control treated animals (n=9; mean difference, 18.25% [95% CI, 25.10% to 11.39%]; P<0.001). CONCLUSIONS The upregulation of miR-152 expression in the failing myocardium contributes to HF pathophysiology. Preclinical evidence suggests that miR-152 inhibition preserves cardiac function in a model of pressure overload-induced HF. These findings offer new insights into the pathophysiology of HF and point to miR-152-Glrx5 axis as a potential novel therapeutic target.
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Affiliation(s)
- Thomas J LaRocca
- Division of Critical Care Medicine, Department of Pediatrics, Lucile Packard Children's Hospital (T.J.L.), Stanford University School of Medicine, CA
| | - Timon Seeger
- Stanford Cardiovascular Institute (T.S., I.P.-G., E.N., M.A., J.C.W., I.K.), Stanford University School of Medicine, CA
| | - Maricela Prado
- Department of Cardiothoracic Surgery (M.P., I.P.-G., I.K.), Stanford University School of Medicine, CA
| | - Isaac Perea-Gil
- Department of Cardiothoracic Surgery (M.P., I.P.-G., I.K.), Stanford University School of Medicine, CA.,Stanford Cardiovascular Institute (T.S., I.P.-G., E.N., M.A., J.C.W., I.K.), Stanford University School of Medicine, CA
| | - Evgenios Neofytou
- Stanford Cardiovascular Institute (T.S., I.P.-G., E.N., M.A., J.C.W., I.K.), Stanford University School of Medicine, CA
| | | | - Mohamed Ameen
- Stanford Cardiovascular Institute (T.S., I.P.-G., E.N., M.A., J.C.W., I.K.), Stanford University School of Medicine, CA
| | - Alex Chia Yu Chang
- Department of Cardiology and Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China (A.C.Y.C.)
| | - Gaurav Pandey
- Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY (G.P.)
| | - Joseph C Wu
- Stanford Cardiovascular Institute (T.S., I.P.-G., E.N., M.A., J.C.W., I.K.), Stanford University School of Medicine, CA.,Department of Radiology (J.C.W.), Stanford University School of Medicine, CA
| | - Ioannis Karakikes
- Department of Cardiothoracic Surgery (M.P., I.P.-G., I.K.), Stanford University School of Medicine, CA.,Stanford Cardiovascular Institute (T.S., I.P.-G., E.N., M.A., J.C.W., I.K.), Stanford University School of Medicine, CA
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Abstract
Cardiovascular diseases are one of the most common causes of death in both developing and developed countries worldwide. Even though there have been improvements in primary prevention, the prevalence of cardiovascular diseases continues to increase in recent years. Hence, it is crucial to both investigate the molecular pathophysiology of cardiovascular diseases in-depth and find novel biomarkers regarding the early and proper prevention and diagnosis of these diseases. MicroRNAs, or miRNAs, are endogenous, conserved, single-stranded non-coding RNAs of 21-25 nucleotides in length. miRNAs have important roles in various cellular events such as embryogenesis, proliferation, vasculogenesis, apoptosis, cell growth, differentiation, and tumorigenesis. They also have potential roles in the cardiovascular system, including angiogenesis, cardiac cell contractility, control of lipid metabolism, plaque formation, the arrangement of cardiac rhythm, and cardiac cell growth. Circulating miRNAs are promising novel biomarkers for purposes of the diagnosis and prognosis of cardiovascular diseases. Cell or tissue specificity, stability in serum or plasma, resistance to degradative factors such as freeze-thaw cycles or enzymes in the blood, and fast-release kinetics, provide the potential for miRNAs to be surrogate markers for the early and accurate diagnosis of disease and for predicting middle- or long-term prognosis. Moreover, it may be a logical approach to combine miRNAs with traditional biomarkers to improve risk stratification and long-term prognosis. In addition to their efficacy in both diagnosis and prognosis, miRNA-based therapeutics may be beneficial for treating cardiovascular diseases using novel platforms and computational tools and in combination with traditional methods of analysis. microRNAs are promising, novel therapeutic agents, which can affect multiple genes using different signaling pathways. miRNAs therapeutic modulation techniques have been used in the settings of atherosclerosis, acute myocardial infarction, restenosis, vascular remodeling, arrhythmias, hypertrophy and fibrosis, angiogenesis and cardiogenesis, aortic aneurysm, pulmonary hypertension, and ischemic injury. This review presents detailed information about miRNAs regarding structure and biogenesis, stages of synthesis and functions, expression profiles in serum/plasma of living organisms, diagnostic and prognostic potential as novel biomarkers, and therapeutic applications in various diseases.
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Affiliation(s)
| | - Mehmet Demir
- Department of Cardiology, University of Health Sciences, Bursa Yüksek İhtisas Research and Training Hospital, Bursa, Turkey
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Kura B, Szeiffova Bacova B, Kalocayova B, Sykora M, Slezak J. Oxidative Stress-Responsive MicroRNAs in Heart Injury. Int J Mol Sci 2020; 21:E358. [PMID: 31948131 PMCID: PMC6981696 DOI: 10.3390/ijms21010358] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/31/2019] [Accepted: 01/03/2020] [Indexed: 02/07/2023] Open
Abstract
Reactive oxygen species (ROS) are important molecules in the living organisms as a part of many signaling pathways. However, if overproduced, they also play a significant role in the development of cardiovascular diseases, such as arrhythmia, cardiomyopathy, ischemia/reperfusion injury (e.g., myocardial infarction and heart transplantation), and heart failure. As a result of oxidative stress action, apoptosis, hypertrophy, and fibrosis may occur. MicroRNAs (miRNAs) represent important endogenous nucleotides that regulate many biological processes, including those involved in heart damage caused by oxidative stress. Oxidative stress can alter the expression level of many miRNAs. These changes in miRNA expression occur mainly via modulation of nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuins, calcineurin/nuclear factor of activated T cell (NFAT), or nuclear factor kappa B (NF-κB) pathways. Up until now, several circulating miRNAs have been reported to be potential biomarkers of ROS-related cardiac diseases, including myocardial infarction, hypertrophy, ischemia/reperfusion, and heart failure, such as miRNA-499, miRNA-199, miRNA-21, miRNA-144, miRNA-208a, miRNA-34a, etc. On the other hand, a lot of studies are aimed at using miRNAs for therapeutic purposes. This review points to the need for studying the role of redox-sensitive miRNAs, to identify more effective biomarkers and develop better therapeutic targets for oxidative-stress-related heart diseases.
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Affiliation(s)
- Branislav Kura
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia; (B.K.); (B.S.B.); (B.K.); (M.S.)
| | - Barbara Szeiffova Bacova
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia; (B.K.); (B.S.B.); (B.K.); (M.S.)
| | - Barbora Kalocayova
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia; (B.K.); (B.S.B.); (B.K.); (M.S.)
| | - Matus Sykora
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia; (B.K.); (B.S.B.); (B.K.); (M.S.)
- Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University, 842 15 Bratislava, Slovakia
| | - Jan Slezak
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia; (B.K.); (B.S.B.); (B.K.); (M.S.)
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Cell-Based Mechanosensation, Epigenetics, and Non-Coding RNAs in Progression of Cardiac Fibrosis. Int J Mol Sci 2019; 21:ijms21010028. [PMID: 31861579 PMCID: PMC6982012 DOI: 10.3390/ijms21010028] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/11/2019] [Accepted: 12/15/2019] [Indexed: 12/22/2022] Open
Abstract
The heart is par excellence the 'in-motion' organ in the human body. Compelling evidence shows that, besides generating forces to ensure continuous blood supply (e.g., myocardial contractility) or withstanding passive forces generated by flow (e.g., shear stress on endocardium, myocardial wall strain, and compression strain at the level of cardiac valves), cells resident in the heart respond to mechanical cues with the activation of mechanically dependent molecular pathways. Cardiac stromal cells, most commonly named cardiac fibroblasts, are central in the pathologic evolution of the cardiovascular system. In their normal function, these cells translate mechanical cues into signals that are necessary to renew the tissues, e.g., by continuously rebuilding the extracellular matrix being subjected to mechanical stress. In the presence of tissue insults (e.g., ischemia), inflammatory cues, or modifiable/unmodifiable risk conditions, these mechanical signals may be 'misinterpreted' by cardiac fibroblasts, giving rise to pathology programming. In fact, these cells are subject to changing their phenotype from that of matrix renewing to that of matrix scarring cells-the so-called myo-fibroblasts-involved in cardiac fibrosis. The links between alterations in the abilities of cardiac fibroblasts to 'sense' mechanical cues and molecular pathology programming are still under investigation. On the other hand, various evidence suggests that cell mechanics may control stromal cells phenotype by modifying the epigenetic landscape, and this involves specific non-coding RNAs. In the present contribution, we will provide examples in support of this more integrated vision of cardiac fibrotic progression based on the decryption of mechanical cues in the context of epigenetic and non-coding RNA biology.
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Yu Y, Sun J, Wang R, Liu J, Wang P, Wang C. Curcumin Management of Myocardial Fibrosis and its Mechanisms of Action: A Review. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:1675-1710. [PMID: 31786946 DOI: 10.1142/s0192415x19500861] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Myocardial fibrosis is implicated as a leading risk factor for heart failure, arrhythmia, and sudden death after cardiac injury, as the excessive interstitial extracellular matrix impedes heart contraction and electrical conduction. Complicated mechanisms involving oxidative stress, pro-inflammatory cytokines, chemokine families, NLRP3 inflammasomes, growth factors, and non-coding RNAs participate in cardiac fibrogenesis and make it difficult to designate specific and effective therapies. Oriental herbs have been popular for thousands of years in the health care of Asian residents, due to their multi-targeted, multi-faceted approaches and their multi-functional effects in fighting difficult and complicated diseases, including cardiovascular disorders such as myocardial fibrosis. Curcumin, a natural polyphenol and yellow pigment obtained from the spice turmeric, was found to have strong anti-oxidant and anti-inflammatory properties. Increasing evidence has shown that curcumin can be used to prevent and treat myocardial fibrosis, when the myocardium suffers pathological pro-fibrotic changes in vivo and in vitro. The present review focuses on recent studies elucidating the mechanisms of curcumin in treating different pathologic conditions, including ischemia, hypoxia/reoxygenation, pressure or volume overload, and hyperglycemia or high-fat-induced cardiac fibrosis. Novel analogs such as C66, B2BrBC, Y20, and J17 have been designed to maximize the therapeutic potentials of curcumin. These optimized curcumin analogs with improved bioavailability and pharmacokinetic profiles need to be clinically verified before curcumin could be recommended for the treatment of myocardial fibrosis.
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Affiliation(s)
- Yonghui Yu
- Department of Traditional Chinese Medicine, China-Japan Friendship Hospital, Beijing 100029, P. R. China
| | - Jinghui Sun
- Graduate School of China Academy of Chinese Medical Science, Beijing 100700, P. R. China
| | - Ru Wang
- Graduate School of China Academy of Chinese Medical Science, Beijing 100700, P. R. China
| | - Jiangang Liu
- Center for Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing 100091, P. R. China
| | - Peili Wang
- Center for Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing 100091, P. R. China
| | - Chenglong Wang
- Center for Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Science, Beijing 100091, P. R. China
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Quiñones-Lombraña A, Blanco JG. Comparative analysis of the DYRK1A-SRSF6-TNNT2 pathway in myocardial tissue from individuals with and without Down syndrome. Exp Mol Pathol 2019; 110:104268. [PMID: 31201803 PMCID: PMC6754281 DOI: 10.1016/j.yexmp.2019.104268] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 05/22/2019] [Accepted: 06/11/2019] [Indexed: 10/26/2022]
Abstract
Down syndrome (trisomy 21) is characterized by genome-wide imbalances that result in a range of phenotypic manifestations. Altered expression of DYRK1A in the trisomic context has been linked to some Down syndrome phenotypes. DYRK1A regulates the splicing of cardiac troponin (TNNT2) through a pathway mediated by the master splicing factor SRSF6. Here, we documented the expression of the DYRK1A-SRSF6-TNNT2 pathway in a collection of myocardial samples from persons with and without Down syndrome. Results suggest that "gene dosage effect" may drive the expression of DYRK1A mRNA but has no effect on DYRK1A protein levels in trisomic myocardium. The levels of phosphorylated DYRK1A-Tyr321 tended to be higher (~35%) in myocardial samples from donors with Down syndrome. The levels of phosphorylated SRSF6 were 2.6-fold higher in trisomic myocardium. In line, the expression of fetal TNNT2 variants was higher in myocardial tissue with trisomy 21. These data provide a representative picture on the extent of inter-individual variation in myocardial DYRK1A-SRSF6-TNNT2 expression in the context of Down syndrome.
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Affiliation(s)
- Adolfo Quiñones-Lombraña
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York (SUNY), Buffalo, New York, United States of America
| | - Javier G Blanco
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York (SUNY), Buffalo, New York, United States of America.
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