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Sarı-Tunel F, Demirkan A, Vural B, Yıldız CE, Komurcu-Bayrak E. Omics Data Integration Uncovers mRNA-miRNA Interaction Regions in Genes Associated with Chronic Venous Insufficiency. Genes (Basel) 2024; 16:40. [PMID: 39858587 PMCID: PMC11765502 DOI: 10.3390/genes16010040] [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: 11/15/2024] [Revised: 12/20/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Chronic venous insufficiency (CVI), a chronic vascular dysfunction, is a common health problem that causes serious complications such as painful varicose veins and even skin ulcers. Identifying the underlying genetic and epigenetic factors is important for improving the quality of life of individuals with CVI. In the literature, many genes, variants, and miRNAs associated with CVI have been identified through genomic and transcriptomic studies. Despite molecular pathogenesis studies, how the genes associated with CVI are regulated by miRNAs and the effect of variants in binding regions on expression levels are still not fully understood. In this study, previously identified genes, variants, and miRNAs associated with CVI, common variants in the mRNA-miRNA binding regions, were investigated using in silico analyses. Methods: For this purpose, miRNA research tools, MBS (miRNA binding site) database, genome browsers, and the eQTL Calculator in the GTEx portal were used. Results: We identified SNVs associated with CVI that may play a direct role in the miRNA-mediated regulation of the ZNF664, COL1A2, HFE, MDN, MTHFR, SRPX, TDRD5, TSPYL4, VEGFA, and APOE genes. In addition, when the common SNVs in the mRNA binding region of 75 unique CVI related-miRNAs in five candidate genes associated with CVI were examined, seven miRNAs associated with the expression profiles of ABCA1, PIEZO1, and CASZ1 genes were identified. Conclusions: In conclusion, the relationship between genetic markers identified in the literature that play a role in the pathogenesis of the CVI and the expression profiles was evaluated for the first time in the mRNA-miRNA interaction axis.
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Affiliation(s)
- Fatma Sarı-Tunel
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, 34093 Istanbul, Turkey; (F.S.-T.); (B.V.)
- Graduate School Institute of Health Sciences, Istanbul University, 34093 Istanbul, Turkey
| | - Ayse Demirkan
- Section of Statistical Multi-Omics, Department of Clinical and Experimental Medicine, School of Biosciences and Medicine and People-Centred AI Institute, University of Surrey, Guildford GU2 7XH, UK
| | - Burcak Vural
- Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, 34093 Istanbul, Turkey; (F.S.-T.); (B.V.)
| | - Cenk Eray Yıldız
- Department of Cardiovascular Surgery, Institute of Cardiology, Istanbul University-Cerrahpasa, 34098 Istanbul, Turkey;
| | - Evrim Komurcu-Bayrak
- Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, Turkey;
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2
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Wei J, Wang X, Yu D, Tu Y, Yu Y. MicroRNA-mediated autophagy and drug resistance in cancer: mechanisms and therapeutic strategies. Discov Oncol 2024; 15:662. [PMID: 39549162 PMCID: PMC11569378 DOI: 10.1007/s12672-024-01525-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 11/04/2024] [Indexed: 11/18/2024] Open
Abstract
This paper provides an exhaustive overview of the intricate interplay between microRNAs (miRNAs) and autophagy in the context of human cancers, underscoring the pivotal role these non-coding RNAs play in modulating autophagic pathways and their implications for cancer development, progression, and resistance to therapy. MiRNAs, as critical regulators of gene expression post-transcription, influence various biological processes, including autophagy, a catabolic mechanism essential for cellular homeostasis, stress response, and survival. The review meticulously delineates the mechanisms through which miRNAs impact autophagy by targeting specific genes and signaling pathways, thereby affecting cancer cell proliferation, metastasis, and response to chemotherapy. It highlights several miRNAs with dual roles, acting either as oncogenes or tumor suppressors based on the cellular context and the specific autophagic pathways they regulate. The paper further explores the therapeutic potential of targeting miRNA-autophagy axis, offering insights into novel strategies for cancer treatment through modulation of this axis. Emphasizing the complexity of the miRNA-autophagy relationship, the review calls for more in-depth studies to unravel the nuanced regulatory networks between miRNAs and autophagy in cancer, which could pave the way for the development of innovative therapeutic interventions and diagnostic tools.
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Affiliation(s)
- Jinxing Wei
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China
| | - Xianghui Wang
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China
| | - Duo Yu
- Department of Biopharmaceutics School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, China
| | - Yanyang Tu
- Research Center, The Huizhou Central People's Hospital, Guangdong Medical University, No. 41 Eling North Road, Huizhou, Guangdong, China.
| | - Yaoyu Yu
- Department of Neurosurgery, Brain Hospital Affiliated to Tongji University, No.2880, Qixin Road, Shanghai, China.
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3
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Wang C, Yang X, Guo Z, Zhu G, Fan L. Circadian gene CLOCK accelerates atherosclerosis by promoting endothelial autophagy. Biotechnol Genet Eng Rev 2024; 40:1230-1245. [PMID: 36946412 DOI: 10.1080/02648725.2023.2193061] [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: 02/12/2023] [Accepted: 03/15/2023] [Indexed: 03/23/2023]
Abstract
Atherosclerosis (AS) is a chronic inflammatory disease which gives rise to life-threatening complications like ischemic stroke. Rupture of carotid atherosclerotic plaque is the main cause of ischemic stroke. Emerging evidence has demonstrated that disturbed circadian rhythms could accelerate the progression of atherosclerosis by regulating endothelial function. Moreover, our previous study implicated the circadian gene circadian locomotor output cycles kaput (CLOCK) in the pathogenesis of unstable plaques. In this study, we explored the underlying mechanism that CLOCK mediates endothelial cell autophagy involved in the progression of AS. Circadian and autophagy gene expression was analyzed in the GSE41571 dataset and human carotid atherosclerotic plaque samples. Then we used ox-LDL to treat HUVECs, and analyzed CLOCK and autophagy gene in endothelial cells. Besides that, we comprehensively analyzed in vivo experiments to explore the function of CLOCK in autophagy and atherosclerosis using different staining including HE, MT and IF staining. In the dataset and patient samples, CLOCK expression and autophagy were decreased in the unstable plaque group compared with the stable group. Decreased Beclin1, ATG5, LC3, and CLOCK were also observed in HUVECs under oxidative stress condition which also enhances cell proliferation. In vivo, we also found decreasing level of CLOCK, Beclin1, LC3 and ATG5 in ApoE-/- mice compared with WT mice. Silencing of CLOCK in ApoE-/- mice may further aggravate atherosclerosis including decreased cap thickness and collagens. Our findings implicated that downregulation CLOCK would impair endothelial cell autophagy and accelerate atherosclerotic plaque, which provides a novel strategy for treatment of progression in AS.
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Affiliation(s)
- Chen Wang
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaohu Yang
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital Fudan University, Shanghai, China
| | - Zhenyu Guo
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital Fudan University, Shanghai, China
| | - Guanglang Zhu
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital Fudan University, Shanghai, China
| | - Longhua Fan
- Department of Vascular Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Vascular Surgery, Qingpu Branch of Zhongshan Hospital Fudan University, Shanghai, China
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4
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Ni L, Yang L, Lin Y. Recent progress of endoplasmic reticulum stress in the mechanism of atherosclerosis. Front Cardiovasc Med 2024; 11:1413441. [PMID: 39070554 PMCID: PMC11282489 DOI: 10.3389/fcvm.2024.1413441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 06/26/2024] [Indexed: 07/30/2024] Open
Abstract
The research progress of endoplasmic reticulum (ER) stress in atherosclerosis (AS) is of great concern. The ER, a critical cellular organelle, plays a role in important biological processes including protein synthesis, folding, and modification. Various pathological factors may cause ER stress, and sustained or excessive ER stress triggers the unfolded protein response, ultimately resulting in apoptosis and disease. Recently, researchers have discovered the importance of ER stress in the onset and advancement of AS. ER stress contributes to the occurrence of AS through different pathways such as apoptosis, inflammatory response, oxidative stress, and autophagy. Therefore, this review focuses on the mechanisms of ER stress in the development of AS and related therapeutic targets, which will contribute to a deeper understanding of the disease's pathogenesis and provide novel strategies for preventing and treating AS.
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Affiliation(s)
| | | | - Yuanyuan Lin
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
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5
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Walweel N, Aydin O. Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies. ACS OMEGA 2024; 9:27832-27852. [PMID: 38973850 PMCID: PMC11223161 DOI: 10.1021/acsomega.4c02234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/01/2024] [Accepted: 05/30/2024] [Indexed: 07/09/2024]
Abstract
The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.
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Affiliation(s)
- Nada Walweel
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
| | - Omer Aydin
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
- ERNAM-Nanotechnology
Research and Application Center, Erciyes
University, Kayseri 38039, Turkey
- ERKAM-Clinical-Engineering
Research and Implementation Center, Erciyes
University, Kayseri 38030, Turkey
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6
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Hu M, Ladowski JM, Xu H. The Role of Autophagy in Vascular Endothelial Cell Health and Physiology. Cells 2024; 13:825. [PMID: 38786047 PMCID: PMC11120581 DOI: 10.3390/cells13100825] [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: 03/27/2024] [Revised: 04/30/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Autophagy is a highly conserved cellular recycling process which enables eukaryotes to maintain both cellular and overall homeostasis through the catabolic breakdown of intracellular components or the selective degradation of damaged organelles. In recent years, the importance of autophagy in vascular endothelial cells (ECs) has been increasingly recognized, and numerous studies have linked the dysregulation of autophagy to the development of endothelial dysfunction and vascular disease. Here, we provide an overview of the molecular mechanisms underlying autophagy in ECs and our current understanding of the roles of autophagy in vascular biology and review the implications of dysregulated autophagy for vascular disease. Finally, we summarize the current state of the research on compounds to modulate autophagy in ECs and identify challenges for their translation into clinical use.
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Affiliation(s)
| | - Joseph M. Ladowski
- Transplant and Immunobiology Research, Department of Surgery, Duke University, Durham, NC 27710, USA;
| | - He Xu
- Transplant and Immunobiology Research, Department of Surgery, Duke University, Durham, NC 27710, USA;
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7
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Cai H, Meng Z, Yu F. The involvement of ROS-regulated programmed cell death in hepatocellular carcinoma. Crit Rev Oncol Hematol 2024; 197:104361. [PMID: 38626849 DOI: 10.1016/j.critrevonc.2024.104361] [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: 11/04/2023] [Revised: 03/11/2024] [Accepted: 04/10/2024] [Indexed: 04/21/2024] Open
Abstract
Reactive oxidative species (ROS) is a crucial factor in the regulation of cellular biological activity and function, and aberrant levels of ROS can contribute to the development of a variety of diseases, particularly cancer. Numerous discoveries have affirmed that this process is strongly associated with "programmed cell death (PCD)," which refers to the suicide protection mechanism initiated by cells in response to external stimuli, such as apoptosis, autophagy, ferroptosis, etc. Research has demonstrated that ROS-induced PCD is crucial for the development of hepatocellular carcinoma (HCC). These activities serve a dual function in both facilitating and inhibiting cancer, suggesting the existence of a delicate balance within healthy cells that can be disrupted by the abnormal generation of reactive oxygen species (ROS), thereby influencing the eventual advancement or regression of a tumor. In this review, we summarize how ROS regulates PCD to influence the tumorigenesis and progression of HCC. Studying how ROS-induced PCD affects the progression of HCC at a molecular level can help develop better prevention and treatment methods and facilitate the design of more effective preventative and therapeutic strategies.
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Affiliation(s)
- Hanchen Cai
- The First Afliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China
| | - Ziqi Meng
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China; The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China
| | - Fujun Yu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China.
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8
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Witucki Ł, Jakubowski H. Homocysteine metabolites inhibit autophagy by upregulating miR-21-5p, miR-155-5p, miR-216-5p, and miR-320c-3p in human vascular endothelial cells. Sci Rep 2024; 14:7151. [PMID: 38531978 DOI: 10.1038/s41598-024-57750-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 03/21/2024] [Indexed: 03/28/2024] Open
Abstract
Nutritional and genetic deficiencies in homocysteine (Hcy) metabolism lead to hyperhomocysteinemia (HHcy) and cause endothelial dysfunction, a hallmark of atherosclerosis, which is a major cause of cardiovascular disease (CVD). Impaired autophagy causes the accumulation of damaged proteins and organelles and is associated with CVD. Biochemically, HHcy is characterized by elevated levels of Hcy and its metabolites, Hcy-thiolactone and N-Hcy-protein. However, whether these metabolites can dysregulate mTOR signaling and autophagy in endothelial cells is not known. Here, we examined the influence of Hcy-thiolactone, N-Hcy-protein, and Hcy on autophagy human umbilical vein endothelial cells. We found that treatments with Hcy-thiolactone, N-Hcy-protein, or Hcy significantly downregulated beclin 1 (BECN1), autophagy-related 5 (ATG5), autophagy-related 7 (ATG7), and microtubule-associated protein 1 light chain 3 (LC3) mRNA and protein levels. We also found that these changes were mediated by upregulation by Hcy-thiolactone, N-Hcy-protein, and Hcy of autophagy-targeting microRNA (miR): miR-21, miR-155, miR-216, and miR-320c. The effects of these metabolites on levels of miR targeting autophagy as well as on the levels of BECN1, ATG5, ATG7, and LC3 mRNA and protein were abrogated by treatments with inhibitors of miR-21, miR-155, miR-216, and mir320c. Taken together, our findings show that Hcy metabolites can upregulate miR-21, miR-155, miR-216, and mir320c, which then downregulate autophagy in human endothelial cells, important for vascular homeostasis.
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Affiliation(s)
- Łukasz Witucki
- Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, 60-632, Poznań, Poland
| | - Hieronim Jakubowski
- Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, 60-632, Poznań, Poland.
- Department of Microbiology, Biochemistry and Molecular Genetics, New Jersey Medical School, International Center for Public Health, Rutgers University, 225 Warren Street, Newark, NJ, 07103, USA.
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9
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Solanki K, Bezsonov E, Orekhov A, Parihar SP, Vaja S, White FA, Obukhov AG, Baig MS. Effect of reactive oxygen, nitrogen, and sulfur species on signaling pathways in atherosclerosis. Vascul Pharmacol 2024; 154:107282. [PMID: 38325566 DOI: 10.1016/j.vph.2024.107282] [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: 01/28/2024] [Accepted: 02/04/2024] [Indexed: 02/09/2024]
Abstract
Atherosclerosis is a chronic inflammatory disease in which fats, lipids, cholesterol, calcium, proliferating smooth muscle cells, and immune cells accumulate in the intima of the large arteries, forming atherosclerotic plaques. A complex interplay of various vascular and immune cells takes place during the initiation and progression of atherosclerosis. Multiple reports indicate that tight control of reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) production is critical for maintaining vascular health. Unrestricted ROS and RNS generation may lead to activation of various inflammatory signaling pathways, facilitating atherosclerosis. Given these deleterious consequences, it is important to understand how ROS and RNS affect the signaling processes involved in atherogenesis. Conversely, RSS appears to exhibit an atheroprotective potential and can alleviate the deleterious effects of ROS and RNS. Herein, we review the literature describing the effects of ROS, RNS, and RSS on vascular smooth muscle cells, endothelial cells, and macrophages and focus on how changes in their production affect the initiation and progression of atherosclerosis. This review also discusses the contribution of ROS, RNS, and RSS in mediating various post-translational modifications, such as oxidation, nitrosylation, and sulfation, of the molecules involved in inflammatory signaling.
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Affiliation(s)
- Kundan Solanki
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, India
| | - Evgeny Bezsonov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia; Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, Moscow, Russia; Department of Biology and General Genetics, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; The Cell Physiology and Pathology Laboratory, Turgenev State University of Orel, Orel, Russia
| | - Alexander Orekhov
- Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia
| | - Suraj P Parihar
- Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Medical Microbiology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Department of Biochemistry, Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom, South Africa
| | - Shivani Vaja
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, India
| | - Fletcher A White
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Anesthesia, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Alexander G Obukhov
- Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Mirza S Baig
- Department of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, India.
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10
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Xu H, Fu J, Tu Q, Shuai Q, Chen Y, Wu F, Cao Z. The SGLT2 inhibitor empagliflozin attenuates atherosclerosis progression by inducing autophagy. J Physiol Biochem 2024; 80:27-39. [PMID: 37792168 DOI: 10.1007/s13105-023-00974-0] [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: 02/17/2022] [Accepted: 07/10/2023] [Indexed: 10/05/2023]
Abstract
Cardiovascular disease due to atherosclerosis is one of the leading causes of death worldwide; however, the underlying mechanism has yet to be defined. The sodium-dependent glucose transporter 2 inhibitor (SGLT2i) empagliflozin is a new type of hypoglycemic drug. Recent studies have shown that empagliflozin not only reduces high glucose levels but also exerts cardiovascular-protective effects and slows the process of atherosclerosis. The purpose of this study was to elucidate the mechanism by which empagliflozin ameliorates atherosclerosis. Male apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat Western diet to establish an atherosclerosis model. The area and size of atherosclerotic lesions in ApoE-/- mice were then assessed by performing hematoxylin-eosin (HE) staining after empagliflozin treatment. Concurrently, oxidized low-density lipoprotein (oxLDL) was used to mimic atherosclerosis in three different types of cells. Then, following empagliflozin treatment of macrophage cells (RAW264.7), human aortic smooth muscle cells (HASMCs), and human umbilical vein endothelial cells (HUVECs), western blotting was applied to measure the levels of autophagy-related proteins and proinflammatory cytokines, and green fluorescent protein (GFP)-light chain 3 (LC3) puncta were detected using confocal microscopy to confirm autophagosome formation. Oil Red O staining was performed to detect the foaming of macrophages and HASMCs, and flow cytometry was used for the cell cycle analysis. 5-ethynyl-2'-deoxyuridine (EdU), cell counting kit-8 (CCK-8), and scratch assays were also performed to examine the proliferation and migration of HASMCs. Empagliflozin suppressed the progression of atherosclerotic lesions in ApoE-/- mice. Empagliflozin also induced autophagy in RAW246.7 cells, HASMCs, and HUVECs via the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, and it significantly increased the levels of the Beclin1 protein, the LC3B-II/I ratio, and p-AMPK protein. In addition, empagliflozin decreased the expression of P62 and the protein levels of inflammatory cytokines, and it inhibited the foaming of RAW246.7 cells and HASMCs, as well as the expression of inflammatory factors by inducing autophagy. Empagliflozin activated autophagy through the AMPK signaling pathway to delay the progression of atherosclerosis. Furthermore, the results of flow cytometry, EdU assays, CCK-8 cell viability assays, and scratch assays indicated that empagliflozin blocked HASMCs proliferation and migration. Empagliflozin activates autophagy through the AMPK signaling pathway to delay the evolution of atherosclerosis, indicating that it may represent a new and effective drug for the clinical treatment of atherosclerosis.
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Affiliation(s)
- Hualin Xu
- Postgraduate Training Basement of Jinzhou Medical University, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
- Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Jie Fu
- Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Qiang Tu
- Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Qingyun Shuai
- Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Yizhi Chen
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Fuyun Wu
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
| | - Zheng Cao
- Postgraduate Training Basement of Jinzhou Medical University, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China.
- Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
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11
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Kang BA, Li HM, Chen YT, Deng MJ, Li Y, Peng YM, Gao JJ, Mo ZW, Zhou JG, Ou ZJ, Ou JS. High-density lipoprotein regulates angiogenesis by affecting autophagy via miRNA-181a-5p. SCIENCE CHINA. LIFE SCIENCES 2024; 67:286-300. [PMID: 37897614 DOI: 10.1007/s11427-022-2381-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 06/02/2023] [Indexed: 10/30/2023]
Abstract
We previously demonstrated that normal high-density lipoprotein (nHDL) can promote angiogenesis, whereas HDL from patients with coronary artery disease (dHDL) is dysfunctional and impairs angiogenesis. Autophagy plays a critical role in angiogenesis, and HDL regulates autophagy. However, it is unclear whether nHDL and dHDL regulate angiogenesis by affecting autophagy. Endothelial cells (ECs) were treated with nHDL and dHDL with or without an autophagy inhibitor. Autophagy, endothelial nitric oxide synthase (eNOS) expression, miRNA expression, nitric oxide (NO) production, superoxide anion (O2•-) generation, EC migration, and tube formation were evaluated. nHDL suppressed the expression of miR-181a-5p, which promotes autophagy and the expression of eNOS, resulting in NO production and the inhibition of O2•- generation, and ultimately increasing in EC migration and tube formation. dHDL showed opposite effects compared to nHDL and ultimately inhibited EC migration and tube formation. We found that autophagy-related protein 5 (ATG5) was a direct target of miR-181a-5p. ATG5 silencing or miR-181a-5p mimic inhibited nHDL-induced autophagy, eNOS expression, NO production, EC migration, tube formation, and enhanced O2•- generation, whereas overexpression of ATG5 or miR-181a-5p inhibitor reversed the above effects of dHDL. ATG5 expression and angiogenesis were decreased in the ischemic lower limbs of hypercholesterolemic low-density lipoprotein receptor null (LDLr-/-) mice when compared to C57BL/6 mice. ATG5 overexpression improved angiogenesis in ischemic hypercholesterolemic LDLr-/- mice. Taken together, nHDL was able to stimulate autophagy by suppressing miR-181a-5p, subsequently increasing eNOS expression, which generated NO and promoted angiogenesis. In contrast, dHDL inhibited angiogenesis, at least partially, by increasing miR-181a-5p expression, which decreased autophagy and eNOS expression, resulting in a decrease in NO production and an increase in O2•- generation. Our findings reveal a novel mechanism by which HDL affects angiogenesis by regulating autophagy and provide a therapeutic target for dHDL-impaired angiogenesis.
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Affiliation(s)
- Bi-Ang Kang
- Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
- NHC key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, China
- Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
| | - Hua-Ming Li
- Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
- NHC key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, China
- Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
| | - Ya-Ting Chen
- Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
- NHC key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, China
- Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
| | - Meng-Jie Deng
- Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
- NHC key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, China
- Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
| | - Yan Li
- Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
- NHC key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, China
- Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
| | - Yue-Ming Peng
- Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
- NHC key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, China
- Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
| | - Jian-Jun Gao
- Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
- NHC key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, China
- Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
| | - Zhi-Wei Mo
- Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
- NHC key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, China
- Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China
- Division of Vascular Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jia-Guo Zhou
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhi-Jun Ou
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China.
- NHC key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, China.
- Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China.
- Division of Hypertension and Vascular Diseases, Department of Cardiology, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
| | - Jing-Song Ou
- Division of Cardiac Surgery, Cardiovascular Diseases Institute, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China.
- NHC key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, 510080, China.
- Guangdong Provincial Engineering and Technology Center for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080, China.
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
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12
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Marzoog BA. Endothelial Cell Aging and Autophagy Dysregulation. Cardiovasc Hematol Agents Med Chem 2024; 22:413-420. [PMID: 38265402 DOI: 10.2174/0118715257275690231129101408] [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: 08/04/2023] [Revised: 10/26/2023] [Accepted: 11/15/2023] [Indexed: 01/25/2024]
Abstract
Entropy is a natural process that affects all living cells, including senescence, an irreversible physiological process that impairs cell homeostasis. Age is a significant factor in disease development, and the pathogenesis of endothelial cell aging is multifactorial. Autophagy dysfunction accelerates endothelial cell aging and cell death, while autophagy preserves endothelial cell youthfulness through intracellular homeostasis and gene expression regulation. Sirt, mTORC1, and AMPK are youthfulness genes that induce autophagy by inhibiting mTOR and upregulating FIP200/Atg13/ULK1. Aged endothelial cells have decreased levels of Lamin B1, γH2AX, Ki67, BrdU, PCNA, and SA β-Gal. Maintaining healthy young endothelial cells can prevent most cardiovascular diseases. Autophagy targeting is a potential future therapeutic strategy to modify endothelial cell age and potentially slow or reverse the aging process. This article provides state-of-the-art research on the role of autophagy in endothelial cell aging. Hypothesizing that autophagy dysregulation is associated with early endothelial cell dysfunction and further clinical sequelae, including atherosclerosis formation, leading to various cardiovascular diseases.
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Affiliation(s)
- Basheer Abdullah Marzoog
- World-Class Research Center, Digital Biodesign and Personalized Healthcare, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia; Postal Address, 8-2 Trubetskaya Street, 119991, Moscow, Russia
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13
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Pultar M, Oesterreicher J, Hartmann J, Weigl M, Diendorfer A, Schimek K, Schädl B, Heuser T, Brandstetter M, Grillari J, Sykacek P, Hackl M, Holnthoner W. Analysis of extracellular vesicle microRNA profiles reveals distinct blood and lymphatic endothelial cell origins. JOURNAL OF EXTRACELLULAR BIOLOGY 2024; 3:e134. [PMID: 38938681 PMCID: PMC11080916 DOI: 10.1002/jex2.134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 11/22/2023] [Accepted: 12/22/2023] [Indexed: 06/29/2024]
Abstract
Extracellular vesicles (EVs) are crucial mediators of cell-to-cell communication in physiological and pathological conditions. Specifically, EVs released from the vasculature into blood were found to be quantitatively and qualitatively different in diseases compared to healthy states. However, our understanding of EVs derived from the lymphatic system is still scarce. In this study, we compared the mRNA and microRNA (miRNA) expression in blood vascular (BEC) and lymphatic (LEC) endothelial cells. After characterization of the EVs by fluorescence-triggered flow cytometry, nanoparticle tracking analysis and cryo-transmission electron microscopy (cryo-TEM) we utilized small RNA-sequencing to characterize miRNA signatures in the EVs and identify cell-type specific miRNAs in BEC and LEC. We found miRNAs specifically enriched in BEC and LEC on the cellular as well as the extracellular vesicle level. Our data provide a solid basis for further functional in vitro and in vivo studies addressing the role of EVs in the blood and lymphatic vasculature.
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Affiliation(s)
- Marianne Pultar
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
- TAmiRNA GmbHViennaAustria
| | - Johannes Oesterreicher
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | | | - Moritz Weigl
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
- TAmiRNA GmbHViennaAustria
| | | | - Katharina Schimek
- Technische Universität Berlin, Medical BiotechnologyBerlinGermany
- TissUse GmbHBerlinGermany
| | - Barbara Schädl
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
- University Clinic of DentistryMedical University of ViennaViennaAustria
| | - Thomas Heuser
- Vienna Biocenter Core Facilities GmbH, EM FacilityViennaAustria
| | | | - Johannes Grillari
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
- Department of Biotechnology, Institute of Molecular BiotechnologyUniversity of Natural Resources and Life SciencesViennaAustria
| | - Peter Sykacek
- Department of Biotechnology, Institute of Computational BiologyUniversity of Natural Resources and Life SciencesViennaAustria
| | | | - Wolfgang Holnthoner
- Ludwig Boltzmann Institute for TraumatologyThe Research Centre in Cooperation with AUVAViennaAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
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14
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Marzoog BA. Autophagy Behavior in Endothelial Cell Regeneration. Curr Aging Sci 2024; 17:58-67. [PMID: 37861048 DOI: 10.2174/0118746098260689231002044435] [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: 06/28/2023] [Revised: 08/16/2023] [Accepted: 08/25/2023] [Indexed: 10/21/2023]
Abstract
Autophagy plays a crucial role in maintaining endothelial cell homeostasis through the turnover of intracellular components during stress conditions in a lysosomal-dependent manner. The regeneration strategy involves several aspects, including autophagy. Autophagy is a catabolic degenerative lysosomal-dependent degradation of intracellular components. Autophagy modifies cellular and subcellular endothelial cell functions, including mitochondria stress, lysosomal stress, and endoplasmic reticulum unfolded protein response. Activation of common signaling pathways of autophagy and regeneration and enhancement of intracellular endothelial cell metabolism serve as the bases for the induction of endothelial regeneration. Endothelial progenitor cells include induced pluripotent stem cells (iPSC), embryonic stem cells, and somatic cells, such as fibroblasts. Future strategies of endothelial cell regeneration involve the induction of autophagy to minimize the metabolic degeneration of the endothelial cells and optimize the regeneration outcomes.
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Affiliation(s)
- Basheer Abdullah Marzoog
- World-Class Research Center «Digital Biodesign and Personalized Healthcare», I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia
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15
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Peng Y, Liao B, Zhou Y, Zeng W. Ginsenoside Rb2 improves heart failure by down-regulating miR-216a-5p to promote autophagy and inhibit apoptosis and oxidative stress. J Appl Biomed 2023; 21:180-192. [PMID: 38112457 DOI: 10.32725/jab.2023.024] [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: 03/02/2023] [Accepted: 12/05/2023] [Indexed: 12/21/2023] Open
Abstract
BACKGROUND Ginsenoside Rb2 is beneficial in cardiovascular disease treatment, yet its role in heart failure (HF) is obscure. This study aimed to investigate the effect and mechanism of ginsenoside Rb2 on HF. METHODS The left anterior descending branch-ligated HF rat model and oxygen-glucose deprivation/reoxygenation (OGD/R) H9c2 cell model were constructed. Ginsenoside Rb2 were applied for intervention. Heart function indexes, miR-216a-5p expression, autophagy, oxidative stress, apoptosis, cell morphology, and proliferation were detected to explore the effect of ginsenoside Rb2 on HF. Overexpression of miR-216a-5p was employed to explore the specific mechanism of ginsenoside Rb2 on HF. RESULTS Ginsenoside Rb2 improved the heart function of HF rats, including the reduction of heart rate, LVEDP, and heart weight/body weight ratio, and the increase of LVSP, +dP/dtmax, -dP/dtmax, LVEF, and LVFS. It also down-regulated miR-216a-5p expression and enhanced OGD/R-induced cardiomyocyte viability. Ginsenoside Rb2 up-regulated Bcl2, LC3B II/I, and Beclin1, and down-regulated Bax, Caspase-3, and p62 in the myocardium of HF rats and OGD/R-induced H9c2 cells. Moreover, ginsenoside Rb2 increased the levels of SOD and CAT, but decreased the levels of MDA and ROS in the myocardium of HF rats and OGD/R-induced H9c2 cells. However, overexpression of miR-216a-5p promoted the apoptosis and oxidative stress of cardiomyocytes and inhibited autophagy, thus reversing the therapeutic effect of ginsenoside Rb2 on HF in vivo and in vitro. CONCLUSION Ginsenoside Rb2 demonstrated potential as a therapeutic intervention for HF by enhancing autophagy and reducing apoptosis and oxidative stress through miR-216a-5p downregulation. Further research could explore its application in clinical trials and investigate the complex mechanism networks underlying its effects.
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Affiliation(s)
- You Peng
- The First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, Center of Geriatric, Changsha, Hunan, China
- Hunan Research Institute of Geriatrics, Changsha, Hunan, China
- Major Chronic Disease Research Center of Hunan Provincial Geriatric Institute, Changsha, Hunan, China
| | - Bin Liao
- The First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, Center of Geriatric, Changsha, Hunan, China
| | - Yan Zhou
- The First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, Center of Geriatric, Changsha, Hunan, China
| | - Wei Zeng
- The First Affiliated Hospital of Hunan Normal University, Hunan Provincial People's Hospital, Center of Geriatric, Changsha, Hunan, China
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16
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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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17
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Ueno D, Ikeda K, Yamazaki E, Katayama A, Urata R, Matoba S. Spermidine improves angiogenic capacity of senescent endothelial cells, and enhances ischemia-induced neovascularization in aged mice. Sci Rep 2023; 13:8338. [PMID: 37221395 DOI: 10.1038/s41598-023-35447-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 05/18/2023] [Indexed: 05/25/2023] Open
Abstract
Aging is closely associated with the increased morbidity and mortality of ischemic cardiovascular disease, at least partially through impaired angiogenic capacity. Endothelial cells (ECs) play a crucial role in angiogenesis, and their angiogenic capacity declines during aging. Spermidine is a naturally occurring polyamine, and its dietary supplementation has exhibited distinct anti-aging and healthy lifespan-extending effects in various species such as yeast, worms, flies, and mice. Here, we explore the effects of spermidine supplementation on the age-related decline in angiogenesis both in vitro and in vivo. Intracellular polyamine contents were reduced in replicative senescent ECs, which were subsequently recovered by spermidine supplementation. Our findings reveal that spermidine supplementation improved the declined angiogenic capacity of senescent ECs, including migration and tube-formation, without affecting the senescence phenotypes. Mechanistically, spermidine enhanced both autophagy and mitophagy, and improved mitochondrial quality in senescent ECs. Ischemia-induced neovascularization was assessed using the hind-limb ischemia model in mice. Limb blood flow recovery and neovascularization in the ischemic muscle were considerably impaired in aged mice compared to young ones. Of note, dietary spermidine significantly enhanced ischemia-induced angiogenesis, and improved the blood flow recovery in the ischemic limb, especially in aged mice. Our results reveal novel proangiogenic functions of spermidine, suggesting its therapeutic potential against ischemic disease.
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Affiliation(s)
- Daisuke Ueno
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
| | - Koji Ikeda
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan.
- Department of Epidemiology for Longevity and Regional Health, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan.
| | - Ekura Yamazaki
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
| | - Akiko Katayama
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
| | - Ryota Urata
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
| | - Satoaki Matoba
- Department of Cardiology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto, 602-8566, Japan
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18
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Sharma P, Kaushal N, Saleth LR, Ghavami S, Dhingra S, Kaur P. Oxidative stress-induced apoptosis and autophagy: Balancing the contrary forces in spermatogenesis. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166742. [PMID: 37146914 DOI: 10.1016/j.bbadis.2023.166742] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 04/18/2023] [Accepted: 04/27/2023] [Indexed: 05/07/2023]
Abstract
Spermatogenesis is a complex process in the testis and is a cornerstone of male infertility. The abundance of unsaturated fatty acid and high cell division rate make male germs cells prone to DNA deterioration. ROS-mediated oxidative stress triggers DNA damage, autophagy, and apoptosis in male germ cells, which are critical causative factors that lead to male infertility. The complex connection and molecular crosstalk between apoptosis and autophagy is seen at multifaceted levels that interconnect the signaling pathways of these two processes. Multilevel interaction between apoptosis and autophagy is a seamless state of survival and death in response to various stressors. Interaction between multiple genes and proteins such as the mTor signaling pathway, Atg12 proteins, and the death adapter proteins, such as Beclin 1, p53, and Bcl-2 family proteins, validates such a link between these two phenomena. Testicular cells being epigenetically different from somatic cells, undergo numerous significant epigenetic transitions, and ROS modulates the epigenetic framework of mature sperm. Epigenetic deregulation of apoptosis and autophagy under oxidative stress conditions can cause sperm cell damage. The current review recapitulates the current role of prevailing stressors that generate oxidative stress leading to the induction of apoptosis and autophagy in the male reproductive system. Considering the pathophysiological consequences of ROS-mediated apoptosis and autophagy, a combinatorial approach, including apoptosis inhibition and autophagy activation, a therapeutic strategy to treat male idiopathic infertility. Understanding the crosslink between apoptosis and autophagy under stress conditions in male germ cells may play an essential role in developing therapeutic strategies to treat infertility.
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Affiliation(s)
- Parul Sharma
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala, Punjab 147004, India
| | - Naveen Kaushal
- Department of Biophysics, Panjab University, Chandigarh 160014, India
| | - Leena Regi Saleth
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Research Institute of Hematology and Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Sanjiv Dhingra
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada
| | - Parminder Kaur
- Department of Biotechnology, University Institute of Engineering & Technology, Panjab University, Chandigarh 160024, India.
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19
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Alidadi M, Hjazi A, Ahmad I, Mahmoudi R, Sarrafha M, Reza Hosseini-Fard S, Ebrahimzade M. Exosomal non-coding RNAs: Emerging therapeutic targets in atherosclerosis. Biochem Pharmacol 2023; 212:115572. [PMID: 37127247 DOI: 10.1016/j.bcp.2023.115572] [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: 02/25/2023] [Revised: 04/09/2023] [Accepted: 04/24/2023] [Indexed: 05/03/2023]
Abstract
Atherosclerosis is an LDL-driven and inflammatory disorder of the sub-endothelial space. Available data have proposed that various factors could affect atherosclerosis pathogenesis, including inflammation, oxidation of LDL particles, endothelial dysfunction, foam cell formation, proliferation, and migration of vascular smooth muscle cells (VSMCs). In addition, other research indicated that the crosstalk among atherosclerosis-induced cells is a crucial factor in modulating atherosclerosis. Extracellular vesicles arenanoparticleswith sizes ranging from 30-150 nm, playing an important role in various pathophysiological situations. Exosomes, asa form of extracellular vesicles, could affect the crosstalk between sub-endothelial cells. They can transport bioactive components like proteins, lipids, RNA, and DNA. As an important cargo in exosomes, noncoding RNAs (ncRNAs) including microRNAs, long noncoding RNAs, and circular RNAs could modulate cellular functions by regulating the transcription, epigenetic alteration, and translation. The current work aimed to investigate the underlying molecular mechanisms of exosomal ncRNA as well as their potential as a diagnostic biomarker and therapeutic target in atherosclerosis.
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Affiliation(s)
- Mahdi Alidadi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Reza Mahmoudi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Sarrafha
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Reza Hosseini-Fard
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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20
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Zhao F, Satyanarayana G, Zhang Z, Zhao J, Ma XL, Wang Y. Endothelial Autophagy in Coronary Microvascular Dysfunction and Cardiovascular Disease. Cells 2022; 11:2081. [PMID: 35805165 PMCID: PMC9265562 DOI: 10.3390/cells11132081] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/22/2022] [Accepted: 06/28/2022] [Indexed: 02/06/2023] Open
Abstract
Coronary microvascular dysfunction (CMD) refers to a subset of structural and/or functional disorders of coronary microcirculation that lead to impaired coronary blood flow and eventually myocardial ischemia. Amid the growing knowledge of the pathophysiological mechanisms and the development of advanced tools for assessment, CMD has emerged as a prevalent cause of a broad spectrum of cardiovascular diseases (CVDs), including obstructive and nonobstructive coronary artery disease, diabetic cardiomyopathy, and heart failure with preserved ejection fraction. Of note, the endothelium exerts vital functions in regulating coronary microvascular and cardiac function. Importantly, insufficient or uncontrolled activation of endothelial autophagy facilitates the pathogenesis of CMD in diverse CVDs. Here, we review the progress in understanding the pathophysiological mechanisms of autophagy in coronary endothelial cells and discuss their potential role in CMD and CVDs.
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Affiliation(s)
- Fujie Zhao
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | | | - Zheng Zhang
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | - Jianli Zhao
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | - Xin-Liang Ma
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | - Yajing Wang
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
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21
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Mameli E, Martello A, Caporali A. Autophagy at the interface of endothelial cell homeostasis and vascular disease. FEBS J 2022; 289:2976-2991. [PMID: 33934518 DOI: 10.1111/febs.15873] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 03/16/2021] [Accepted: 04/09/2021] [Indexed: 12/19/2022]
Abstract
Autophagy is an essential intracellular process for cellular quality control. It enables cell homeostasis through the selective degradation of harmful protein aggregates and damaged organelles. Autophagy is essential for recycling nutrients, generating energy to maintain cell viability in most tissues and during adverse conditions such as hypoxia/ischaemia. The progressive understanding of the mechanisms modulating autophagy in the vasculature has recently led numerous studies to link intact autophagic responses with endothelial cell (EC) homeostasis and function. Preserved autophagic flux within the ECs has an essential role in maintaining their physiological characteristics, whereas defective autophagy can promote endothelial pro-inflammatory and atherogenic phenotype. However, we still lack a good knowledge of the complete molecular repertoire controlling various aspects of endothelial autophagy and how this is associated with vascular diseases. Here, we provide an overview of the current state of the art of autophagy in ECs. We review the discoveries that have so far defined autophagy as an essential mechanism in vascular biology and analyse how autophagy influences ECs behaviour in vascular disease. Finally, we emphasise opportunities for compounds to regulate autophagy in ECs and discuss the challenges of exploiting them to resolve vascular disease.
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Affiliation(s)
- Eleonora Mameli
- University/BHF Centre for Cardiovascular Science, QMRI, University of Edinburgh, UK
| | | | - Andrea Caporali
- University/BHF Centre for Cardiovascular Science, QMRI, University of Edinburgh, UK
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22
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Marfella R, Federici M, Paolisso G. Editorial: Hyperglycemia and Coronary Artery Diseases: Physio-Pathological Findings and Therapeutic Implications. Front Pharmacol 2022; 13:901815. [PMID: 35662710 PMCID: PMC9161351 DOI: 10.3389/fphar.2022.901815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 04/20/2022] [Indexed: 01/08/2023] Open
Affiliation(s)
- Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
- Mediterraneo Cardiocentro, Napoli, Italy
| | - Massimo Federici
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Giuseppe Paolisso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
- Mediterraneo Cardiocentro, Napoli, Italy
- *Correspondence: Giuseppe Paolisso,
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23
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The lncRNA TCONS_00021785/miR-21-5p/Trim33 axis regulates VMP1-mediated zymophagy, reduces the activation of trypsinogen, and promotes acinar cell recovery. Cell Death Dis 2022; 8:65. [PMID: 35169128 PMCID: PMC8847645 DOI: 10.1038/s41420-022-00862-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 12/31/2021] [Accepted: 02/02/2022] [Indexed: 11/29/2022]
Abstract
In the early stage of acute pancreatitis, trypsinogen in acinar cells is activated, and the cells clear trypsin through zymophagy to avoid damage. Studies have shown that the substrate of zymophagy is ubiquitinated pancreatin, but the mechanism of pancreatin ubiquitination and the regulatory mechanism of zymophagy are not fully understood. Our results show that Trim33 can enhance cell viability, reduce cell necrosis, and reduce trypsinogen activation. Trim33 is a key E3 ligase enzyme that mediates trypsin ubiquitination. The results showed that overexpression of Trim33 can significantly increase VMP1 mRNA and protein levels. However, knocking down Trim33 produced the opposite effect, which indicates that Trim33, as a transcriptional mediator, affects zymophagy by regulating the expression of VMP1. In addition, we explored the transcriptional regulation mechanism of the Trim33 molecule. Our research shows that lncRNA TCONS_00021785 can competitively bind miR-21-5p to upregulate Trim33, thereby initiating enzyme autophagy and reducing zymogen activation.
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24
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Lin L, Zhang MX, Zhang L, Zhang D, Li C, Li YL. Autophagy, Pyroptosis, and Ferroptosis: New Regulatory Mechanisms for Atherosclerosis. Front Cell Dev Biol 2022; 9:809955. [PMID: 35096837 PMCID: PMC8793783 DOI: 10.3389/fcell.2021.809955] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/27/2021] [Indexed: 12/14/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disorder characterized by the gradual buildup of plaques within the vessel wall of middle-sized and large arteries. The occurrence and development of atherosclerosis and the rupture of plaques are related to the injury of vascular cells, including endothelial cells, smooth muscle cells, and macrophages. Autophagy is a subcellular process that plays an important role in the degradation of proteins and damaged organelles, and the autophagy disorder of vascular cells is closely related to atherosclerosis. Pyroptosis is a proinflammatory form of regulated cell death, while ferroptosis is a form of regulated nonapoptotic cell death involving overwhelming iron-dependent lipid peroxidation. Both of them exhibit distinct features from apoptosis, necrosis, and autophagy in morphology, biochemistry, and genetics. However, a growing body of evidence suggests that pyroptosis and ferroptosis interact with autophagy and participate in the development of cancers, degenerative brain diseases and cardiovascular diseases. This review updated the current understanding of autophagy, pyroptosis, and ferroptosis, finding potential links and their effects on atherogenesis and plaque stability, thus providing ways to develop new pharmacological strategies to address atherosclerosis and stabilize vulnerable, ruptured plaques.
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Affiliation(s)
- Lin Lin
- Chinese Medicine Innovation Research Institute, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Mu-Xin Zhang
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lei Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Dan Zhang
- Chinese Medicine Innovation Research Institute, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chao Li
- Chinese Medicine Innovation Research Institute, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yun-Lun Li
- Chinese Medicine Innovation Research Institute, Shandong University of Traditional Chinese Medicine, Jinan, China.,Department of Cardiovascular, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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25
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Chen Q, Zheng Y, Chen X, Ge P, Wang P, Wu B. Upregulation of miR-216a-5p by Lentinan Targeted Inhibition of JAK2/STAT3 Signaling Pathway to Reduce Lung Adenocarcinoma Cell Stemness, Promote Apoptosis, and Slow Down the Lung Adenocarcinoma Mechanisms. Front Oncol 2021; 11:778096. [PMID: 34900727 PMCID: PMC8656221 DOI: 10.3389/fonc.2021.778096] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 10/26/2021] [Indexed: 12/16/2022] Open
Abstract
To investigate the effect of Lentinan (LNT) on lung adenocarcinoma (LUAD) cell stemness and its mechanism. In this study, we founded that LNT significantly reduce the cell proliferation, activity, migration, invasion, and stemness of LUAD cells, and promote their apoptosis compared with the control group in vitro. Moreover, LNT significantly inhibited the volume and weight of tumors of nude mice in vivo. At the same time, LNT can significantly up-regulate miR-216a-5p levels and reduce the protein expression of phospho-JAK2 (Y1007/1008) and phospho-STAT3 (Tyr705), thereby inhibiting the JAK2/STAT3 signaling pathway. Interfering with miR-216a-5p expression and activating the JAK2/STAT3 signaling pathway can significantly reverse LNT inhibitory effects on LUAD. Collectively, LNT can inhibit the JAK2/STAT3 signaling pathway by up-regulating miR-216a-5p, reducing stemness, and promoting LUAD cells apoptosis, then slow down LUAD occurrence and development, providing concepts and experimental foundation treating patients with LUAD.
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Affiliation(s)
- Quan Chen
- Department of Thoracic Surgery, Hospital Affiliated 5 to Nantong University (Taizhou People's Hospital), Taizhou, China
| | - Yiming Zheng
- Department of Thoracic Surgery, Hospital Affiliated 5 to Nantong University (Taizhou People's Hospital), Taizhou, China
| | - Xia Chen
- Department of Thoracic Surgery, Hospital Affiliated 5 to Nantong University (Taizhou People's Hospital), Taizhou, China
| | - Pengfei Ge
- Department of Thoracic Surgery, Hospital Affiliated 5 to Nantong University (Taizhou People's Hospital), Taizhou, China
| | - Pengcheng Wang
- Department of Thoracic Surgery, Hospital Affiliated 5 to Nantong University (Taizhou People's Hospital), Taizhou, China
| | - Bingbing Wu
- Department of Thoracic Surgery, Hospital Affiliated 5 to Nantong University (Taizhou People's Hospital), Taizhou, China
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26
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Gupta R, Ambasta RK, Pravir Kumar. Autophagy and apoptosis cascade: which is more prominent in neuronal death? Cell Mol Life Sci 2021; 78:8001-8047. [PMID: 34741624 PMCID: PMC11072037 DOI: 10.1007/s00018-021-04004-4] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/16/2021] [Accepted: 10/20/2021] [Indexed: 02/06/2023]
Abstract
Autophagy and apoptosis are two crucial self-destructive processes that maintain cellular homeostasis, which are characterized by their morphology and regulated through signal transduction mechanisms. These pathways determine the fate of cellular organelle and protein involved in human health and disease such as neurodegeneration, cancer, and cardiovascular disease. Cell death pathways share common molecular mechanisms, such as mitochondrial dysfunction, oxidative stress, calcium ion concentration, reactive oxygen species, and endoplasmic reticulum stress. Some key signaling molecules such as p53 and VEGF mediated angiogenic pathway exhibit cellular and molecular responses resulting in the triggering of apoptotic and autophagic pathways. Herein, based on previous studies, we describe the intricate relation between cell death pathways through their common genes and the role of various stress-causing agents. Further, extensive research on autophagy and apoptotic machinery excavates the implementation of selective biomarkers, for instance, mTOR, Bcl-2, BH3 family members, caspases, AMPK, PI3K/Akt/GSK3β, and p38/JNK/MAPK, in the pathogenesis and progression of neurodegenerative diseases. This molecular phenomenon will lead to the discovery of possible therapeutic biomolecules as a pharmacological intervention that are involved in the modulation of apoptosis and autophagy pathways. Moreover, we describe the potential role of micro-RNAs, long non-coding RNAs, and biomolecules as therapeutic agents that regulate cell death machinery to treat neurodegenerative diseases. Mounting evidence demonstrated that under stress conditions, such as calcium efflux, endoplasmic reticulum stress, the ubiquitin-proteasome system, and oxidative stress intermediate molecules, namely p53 and VEGF, activate and cause cell death. Further, activation of p53 and VEGF cause alteration in gene expression and dysregulated signaling pathways through the involvement of signaling molecules, namely mTOR, Bcl-2, BH3, AMPK, MAPK, JNK, and PI3K/Akt, and caspases. Alteration in gene expression and signaling cascades cause neurotoxicity and misfolded protein aggregates, which are characteristics features of neurodegenerative diseases. Excessive neurotoxicity and misfolded protein aggregates lead to neuronal cell death by activating death pathways like autophagy and apoptosis. However, autophagy has a dual role in the apoptosis pathways, i.e., activation and inhibition of the apoptosis signaling. Further, micro-RNAs and LncRNAs act as pharmacological regulators of autophagy and apoptosis cascade, whereas, natural compounds and chemical compounds act as pharmacological inhibitors that rescue neuronal cell death through inhibition of apoptosis and autophagic cell death.
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Affiliation(s)
- Rohan Gupta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Mechanical Engineering Building, Delhi Technological University (Formerly Delhi College of Engineering), Room# FW4TF3, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Mechanical Engineering Building, Delhi Technological University (Formerly Delhi College of Engineering), Room# FW4TF3, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Mechanical Engineering Building, Delhi Technological University (Formerly Delhi College of Engineering), Room# FW4TF3, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India.
- , Delhi, India.
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27
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Xu N, Zhao Y, Bu H, Tan S, Dong G, Liu J, Wang M, Jiang J, Yuan B, Li R. Cochlioquinone derivative CoB1 induces cytostatic autophagy in lung cancer through miRNA-125b and Foxp3. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 93:153742. [PMID: 34624808 DOI: 10.1016/j.phymed.2021.153742] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 08/01/2021] [Accepted: 09/07/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Lung cancer is the leading cause of cancer death worldwide, yet no effective medication for this disease is available. Cochlioquinone B derivative (CoB1), purified from Salvia miltiorrhiza endophytic Bipolaris sorokiniana, affects the defense against pulmonary pathogens by regulating inflammatory responses. However, the effect of CoB1 on lung cancer and the underlying molecular mechanisms remain unknown. In the present study, we investigate the protective effects of CoB1 on lung cancer and explore its underlying mechanism. METHOD We examined the inhibitory effect of CoB1 on lung cancer cells (A549 cells) by MTT and colony formation assay. The effect of CoB1 on cytostatic autophagy in lung cancer cells was verified by Western blot, transmission electron microscopy, and confocal microscopy. The differentially expressed miRNAs were identified using quantitative RT-PCR. Luciferase assay and Northern blot were performed to verify the correlation between miRNA-125b and Foxp3. Protein expression in autophagy-related pathways was detected by Western blot. Xenograft tumor models were constructed to explore the inhibitory effect of CoB1 and the role of miRNA-125b as a suppressor in lung cancer in vivo. RESULT CoB1 inhibited lung cancer cell proliferation by inducing cytostatic autophagy both in vitro and in vivo. CoB1-induced autophagy was related to blocking of the PI3K/Akt1/mTOR signaling pathway. In addition, CoB1 induced miR-125b expression via activating the TAK1/MKK4/JNK/Smad axis, thereby reducing Foxp3 expression and further inducing autophagy. CONCLUSION This study is the first to report the specific inhibitory function of CoB1 purified from Salvia miltiorrhiza endophytic Bipolaris sorokiniana in lung cancer, which may be due to the induction of autophagy. This study provides evidence and novel insights into the anticancer efficacy of CoB1.
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Affiliation(s)
- Nana Xu
- Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, P. R. China; Laboratory of Morphology, Xuzhou Medical University, Xuzhou 221004, P. R. China; Jiangsu Medical Engineering Research Center of Gene Detection, Xuzhou Medical University, Xuzhou 221004, P. R. China
| | - Yunyun Zhao
- Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, P. R. China
| | - Huimin Bu
- Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, P. R. China; Department of Physiology, Xuzhou Medical University, Xuzhou 221004, P. R. China
| | - Shirui Tan
- Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming 650500, China
| | - Guokai Dong
- Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, P. R. China; Jiangsu Medical Engineering Research Center of Gene Detection, Xuzhou Medical University, Xuzhou 221004, P. R. China
| | - Jinjuan Liu
- Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, P. R. China
| | - Meng Wang
- Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, P. R. China
| | - Jihong Jiang
- Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, P. R. China
| | - Bo Yuan
- Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, P. R. China.
| | - Rongpeng Li
- Key Laboratory of Biotechnology for Medicinal Plants of Jiangsu Province and School of Life Sciences, Jiangsu Normal University, Xuzhou 221116, P. R. China.
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28
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Lou X, Wang D, Gu Z, Li T, Ren L. Mechanism of microRNA regulating the progress of atherosclerosis in apoE-deficient mice. Bioengineered 2021; 12:10994-11006. [PMID: 34775883 PMCID: PMC8809940 DOI: 10.1080/21655979.2021.2004979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/05/2021] [Accepted: 11/05/2021] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs play important roles in atherosclerogenesis and are important novel pharmaceutic targets in atherosclerosis management. The whole spectrum of miRNAs dysregulation is still under intense investigation. This study intends to identify more novel dysregulated microRNAs in atherosclerotic mice. Half of eight-week-old male ApoE-/- mice were fed with high-fat-diet for 12 weeks as a model mice, and the remaining half of ApoE-/- mice were fed with a normal-diet as a control. A serum lipid profile was performed with ELISA kits, and atherosclerotic lesions were assessed. Aortic tissues were dissected for gene expression profiling using a Multispecies miRNA 4.0 Array, and significant differentially expressed miRNAs were identified with fold change ≥ 2 and p < 0.05. Real-time quantitative PCR was used to validate microarray gene expression data on selected genes. Predicted target genes were extracted and subjected to bioinformatic analysis for molecular function and pathway enrichment analysis. Model mice showed a 15.32% atherosclerotic lesion compared to 1.52% in the control group. A total of 25 significant differentially expressed microRNAs were identified, with most of them (24/25) downregulated. Real-time quantitative PCR confirmed the GeneChip data. Bioinformatic analysis of predicted target genes identified high involvement of the PI3K/Akt/mTOR signaling pathway. Microarray profiling of miRNAs in high-fat-fed Model mice identified 25 differentially expressed miRNAs, including some novel miRNAs, and the PI3K/Akt/mTOR signaling pathway is highly enriched in the predicted target genes. The novel identified dysregulated miRNAs suggest a broader spectrum of miRNA dysregulation in the progression of atherosclerosis and provide more research and therapeutic targets for atherosclerosis.
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Affiliation(s)
- Xiaoqian Lou
- Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Changchun, Jilin, China
- Department of Endocrinology, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Dawei Wang
- Department of Emergency, The First Hospital of Jilin University, Changchun, Jilin, People's Republic of China
| | - Zehui Gu
- Department of Pathology, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, People's Republic of China
| | - Tengteng Li
- Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Changchun, Jilin, China
| | - Liqun Ren
- Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Changchun, Jilin, China
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29
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Hou J, Deng Q, Deng X, Zhong W, Liu S, Zhong Z. MicroRNA-146a-5p alleviates lipopolysaccharide-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production via the regulation of TRAF6 and IRAK1 in human umbilical vein endothelial cells (HUVECs). ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1433. [PMID: 34733985 PMCID: PMC8506750 DOI: 10.21037/atm-21-3903] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 08/30/2021] [Indexed: 01/02/2023]
Abstract
Background Microribonucleic acids (miRNAs) have an evident role in regulating endothelial inflammation and dysfunction, which characterizes the early stages of atherosclerosis. The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome has been reported to contribute to the endothelial inflammatory response that promotes atherosclerosis development and progression. This study sought to investigate the effects of miR-146a-5p on lipopolysaccharide (LPS)-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production in human umbilical vein endothelial cells (HUVECs). Methods HUVECs were transfected with a miR-146a-5p mimic, small-interfering RNA (siRNA) (si-TRAF6, and si-IRAK1), and were then stimulated with LPS for 24 h. The messenger (mRNA) and the protein levels of p-NF-κB/NF-κB, NLRP3, Caspase-1, pro-inflammatory cytokine [interleukin (IL)-6, IL-1β and tumor necrosis factor alpha (TNF-α)] in the HUVECs were analyzed by quantitative real-time polymerase chain reactions (PCRs) and western blot assays, respectively. The secretion of IL-6 from the cells was detected by enzyme-linked immunoassay (ELISA). Bioinformatic and dual-luciferase reporter assays were performed to identify the targets of miR-146a-5p. Results LPS promoted pro-inflammatory cytokine expression in a dose-dependent manner and significantly increased the expression levels of p-NF-κB/NF-κB p65, NLRP3, and Caspase-1. After transfection with a miR-146a-5p mimic, or si-TRAF6 or si-IRAK1, we observed that the mRNA and protein levels of NF-κB/p-NF-κB, NLRP3, Caspase-1, and pro-inflammatory cytokine in the HUVECs were all down-regulated, and the secretion of IL-6 from cells declined significantly. After transfection with a miR-146-5p mimic, the expression of TRAF6 and IRAK1 in HUVECs were both down-regulated. Dual-luciferase reporter assays confirmed that miR-146-5p directly targets the 3'-untranslated region (3'-UTR) of TRAF6 and IRAK1 to regulate their expression. Conclusions As a modulator of TRAF6 and IRAK1, miR-146a-5p negatively regulated LPS-induced NF-κB activation and the NLRP3 inflammasome signaling pathway in HUVECs. Thus, miRNA-146a-5p may serve as a potential therapeutic target for atherosclerosis.
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Affiliation(s)
- Jingyuan Hou
- Meizhou Academy of Medical Sciences Cardiovascular Disease Research Institute, Meizhou People's Hospital, Meizhou, China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, China.,Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases, Meizhou, China
| | - Qiaoting Deng
- Meizhou Academy of Medical Sciences Cardiovascular Disease Research Institute, Meizhou People's Hospital, Meizhou, China.,Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases, Meizhou, China.,Guangdong Provincial Engineering and Technological Research Center for Clinical Molecular Diagnosis and Antibody Drugs, Meizhou, China
| | - Xunwei Deng
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, China.,Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases, Meizhou, China.,Guangdong Provincial Engineering and Technological Research Center for Clinical Molecular Diagnosis and Antibody Drugs, Meizhou, China
| | - Wei Zhong
- Meizhou Academy of Medical Sciences Cardiovascular Disease Research Institute, Meizhou People's Hospital, Meizhou, China
| | - Sudong Liu
- Meizhou Academy of Medical Sciences Cardiovascular Disease Research Institute, Meizhou People's Hospital, Meizhou, China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, China
| | - Zhixiong Zhong
- Meizhou Academy of Medical Sciences Cardiovascular Disease Research Institute, Meizhou People's Hospital, Meizhou, China
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30
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Wang Y, Xue M, Xia F, Zhu L, Jia D, Gao Y, Li L, Shi Y, Li Y, Chen S, Xu G, Yuan C. Long noncoding RNA GAS5 in age-related diseases. Curr Med Chem 2021; 29:2863-2877. [PMID: 34711157 DOI: 10.2174/0929867328666211027123932] [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: 05/01/2021] [Revised: 08/18/2021] [Accepted: 09/01/2021] [Indexed: 11/22/2022]
Abstract
Aging refers to a natural process and a universal phenomenon in all cells, tissues, organs and the whole organism. Long non-coding RNAs (lncRNAs) are non-coding RNAs with the length of 200 nucleotides. LncRNA growth arrest-specific 5 (lncRNA GAS5) is often down-regulated in cancer. The accumulation of lncRNA GAS5 has been found to be able to inhibit cancer growth, invasion and metastasis, while enhancing the sensitivity of cells to chemotherapy drugs. LncRNA GAS5 can be a signaling protein, which is specifically transcribed under different triggering conditions. Subsequently, it is involved in signal transmission in numerous pathways as a signal node. LncRNA GAS5, with a close relationship to multiple miRNAs, was suggested to be involved in the signaling pathway under three action modes (i.e., signal, bait and guidance). LncRNA GAS5 was found to be involved in different age-related diseases (e.g., rheumatoid arthritis, type 2 diabetes, atherosclerosis, osteoarthritis, osteoporosis, multiple sclerosis, cancer etc.). This study mainly summarized the regulatory effect exerted by lncRNA GAS5 on age-related diseases.
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Affiliation(s)
- Yaqi Wang
- College of Medical Science, China Three Gorges University, Yichang 443002. China
| | - Mengzhen Xue
- College of Medical Science, China Three Gorges University, Yichang 443002. China
| | - Fangqi Xia
- College of Medical Science, China Three Gorges University, Yichang 443002. China
| | - Leiqi Zhu
- College of Medical Science, China Three Gorges University, Yichang 443002. China
| | - Dengke Jia
- College of Medical Science, China Three Gorges University, Yichang 443002. China
| | - Yan Gao
- College of Medical Science, China Three Gorges University, Yichang 443002. China
| | - Luoying Li
- College of Medical Science, China Three Gorges University, Yichang 443002. China
| | - Yue Shi
- College of Medical Science, China Three Gorges University, Yichang 443002. China
| | - Yuanyang Li
- College of Medical Science, China Three Gorges University, Yichang 443002. China
| | - Silong Chen
- College of Medical Science, China Three Gorges University, Yichang 443002. China
| | - Guangfu Xu
- College of Medical Science, China Three Gorges University, Yichang 443002. China
| | - Chengfu Yuan
- College of Medical Science, China Three Gorges University, Yichang 443002. China
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31
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Yu C, Wu B, Jiang J, Yang G, Weng C, Cai F. Overexpressed lncRNA ROR Promotes the Biological Characteristics of ox-LDL-Induced HUVECs via the let-7b-5p/HOXA1 Axis in Atherosclerosis. Front Cardiovasc Med 2021; 8:659769. [PMID: 34589524 PMCID: PMC8473629 DOI: 10.3389/fcvm.2021.659769] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 08/04/2021] [Indexed: 02/06/2023] Open
Abstract
The long non-coding RNA regulator of reprogramming (lncRNA ROR) is involved in atherosclerosis (AS), but the specific mechanism remains unclear. The expressions of lncRNA ROR, let-7b-5p, Homeobox A1 (HOXA1), and apoptosis-associated proteins in the serum of AS patients and human umbilical vein endothelial cells (HUVECs) were determined by quantitative real-time PCR (qRT-PCR) and Western blot. The relationships of lncRNA ROR, let-7b-5p, and HOXA1 were analyzed by Pearson's correlation test. The viability and the migration of HUVECs were measured by Cell Counting Kit-8, wound healing, and Transwell assays. The predicted target gene and the potential binding sites were confirmed by dual-luciferase reporter assay. lncRNA ROR was highly expressed in AS, which promoted the cell viability and migration of HUVECs, while lncRNA ROR silencing produced the opposite results. The expression of let-7b-5p, which bound to lncRNA ROR, was downregulated in AS, indicating that the two genes were negatively correlated. Besides this, let-7b-5p reversed the effects of upregulated lncRNA ROR expression on let-7b-5p expression, cell viability, and migration as well as the expressions of apoptosis-related proteins of ox-LDL-treated HUVECs. HOXA1 was targeted by let-7b-5p and upregulated in AS, with its expression being negatively correlated with let-7b-5p but positively correlated with lncRNA ROR. In ox-LDL-treated HUVECs, overexpressed HOXA1 reversed the effects of let-7b-5p, and HOXA1 silencing reversed the effects of lncRNA ROR. In AS, lncRNA ROR promoted the biological characteristics of oxidation of low-density lipoprotein-induced HUVECs via the let-7b-5p/HOXA1 axis.
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Affiliation(s)
- Cong Yu
- Department of Vascular Surgery, Vascular Interventional Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Bin Wu
- Department of Surgery, Pinghu Traditional Chinese Medicine Hospital, Pinghu, China
| | - Jinsong Jiang
- Department of Vascular Surgery, Vascular Interventional Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Guangwei Yang
- Department of Vascular Surgery, Vascular Interventional Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Chao Weng
- Department of Vascular Surgery, Vascular Interventional Center, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Fei Cai
- Department of Vascular Surgery, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Jia P, Huang B, You Y, Su H, Gao L. Ketogenic diet aggravates kidney dysfunction by exacerbating metabolic disorders and inhibiting autophagy in spontaneously hypertensive rats. Biochem Biophys Res Commun 2021; 573:13-18. [PMID: 34375764 DOI: 10.1016/j.bbrc.2021.08.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 08/02/2021] [Indexed: 11/26/2022]
Abstract
AIMS To assess the effects of a ketogenic diet on metabolism and renal fibrosis in spontaneously hypertensive rats. MATERIALS AND METHODS Male spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats were randomly divided into a ketogenic diet group and a normal diet group. Blood glucose and metabolites were measured after 4 weeks. Renal autophagy-related protein expression was detected by Western blot, and renal fibrosis was detected by Masson staining. RESULTS Compared with the normal diet, the ketogenic diet led to significantly decreased glucose tolerance and metabolism; overactivated the renin-angiotensin-aldosterone system; and reduced renal autophagy-related protein expression in SHRs; Masson staining and other experiments showed that the ketogenic diet had no significant effect on hypertensive renal fibrosis. CONCLUSION A Ketogenic diet could lead to disorders of glucose and lipid metabolism, increase hypertension by activating the RAAS, reduce renal autophagy levels and aggravate renal parenchymal damage. Therefore, a ketogenic diet, as a kind of natural therapy, should be vigilantly monitored to prevent further damage in patients with hypertension.
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Affiliation(s)
- Ping Jia
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Bi Huang
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yuehua You
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Hong Su
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Lingyun Gao
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Huang J, Wang FH, Wang L, Li Y, Lu J, Chen J. LncRNA MALAT1 promotes proliferation and migration of airway smooth muscle cells in asthma by downregulating microRNA-216a. Saudi J Biol Sci 2021; 28:4124-4131. [PMID: 34354391 PMCID: PMC8324955 DOI: 10.1016/j.sjbs.2021.03.076] [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: 11/14/2020] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 11/28/2022] Open
Abstract
Asthma is a difficult chronic airway inflammation, if it cannot be treated and relieved in time, it will seriously affect the health and quality of life of patients. Airway remodeling is relevant to asthma, but there is currently no effective treatment for airway remodeling. Regulating the biological function of airway smooth muscle cells (AMSCs) may be an important method to inhibit airway remodeling. LncRNA MALAT1 and microRNA-216a are involved in the regulation of AMSCs respectively, but there is no research to prove that they can regulate airway remodeling of asthma through mutual combination. Hence, the aim of the present study was performed to investigate the function of lncRNA MALAT1 and microRNA-216a on AMSCs in asthma. The relationship between lncRNA MALAT1, microRNA-216a and AMSCs was studied by MTT, qPCR, Western blot, Transwell and flow cytometry. The results revealed that lncRNA MALAT1 was up-regulated and microRNA-216a was down-regulated in asthma. lncRNA MALAT1 inhibited microRNA-216a targetedly. Whether downregulating lncRNA MALAT1 or upregulating microRNA-216a, cell proliferation, migration and invasion were reduced and apoptosis increased. Therefore, it is believed that lncRNA MALAT1 promotes proliferation and migration of asthma AMSCs by downregulating microRNA-216a. Since lncRNA MALAT1 and microRNA-216a take part in asthma by jointly regulating the proliferation of airway smooth muscle cells and other biological functions, it would be interesting to study if they become biomarkers of asthma, and relationship between the two in asthma diagnosis and poor prognosis.
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Affiliation(s)
- Jun Huang
- Qingdao Chengyang District People's Hospital, Qingdao, Shandong 266600, PR China
| | - Fang Hun Wang
- Qingdao Chengyang District People's Hospital, Qingdao, Shandong 266600, PR China
| | - Long Wang
- Qingdao Chengyang District People's Hospital, Qingdao, Shandong 266600, PR China
| | - Yong Li
- Qingdao Chengyang District People's Hospital, Qingdao, Shandong 266600, PR China
| | - Junlimeng Lu
- Department of Respiratory and Critical Medicine, QingDao Chengyang District People's Hospital, Qingdao, Shandong 266600, PR China
| | - JianYou Chen
- Qingdao Chengyang District People's Hospital, Qingdao, Shandong 266600, PR China
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SREBP-1c impairs ULK1 sulfhydration-mediated autophagic flux to promote hepatic steatosis in high-fat-diet-fed mice. Mol Cell 2021; 81:3820-3832.e7. [PMID: 34233158 DOI: 10.1016/j.molcel.2021.06.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/21/2021] [Accepted: 05/30/2021] [Indexed: 12/19/2022]
Abstract
A metabolic imbalance between lipid synthesis and degradation can lead to hepatic lipid accumulation, a characteristic of patients with non-alcoholic fatty liver disease (NAFLD). Here, we report that high-fat-diet-induced sterol regulatory element-binding protein (SREBP)-1c, a key transcription factor that regulates lipid biosynthesis, impairs autophagic lipid catabolism via altered H2S signaling. SREBP-1c reduced cystathionine gamma-lyase (CSE) via miR-216a, which in turn decreased hepatic H2S levels and sulfhydration-dependent activation of Unc-51-like autophagy-activating kinase 1 (ULK1). Furthermore, Cys951Ser mutation of ULK1 decreased autolysosome formation and promoted hepatic lipid accumulation in mice, suggesting that the loss of ULK1 sulfhydration was directly associated with the pathogenesis of NAFLD. Moreover, silencing of CSE in SREBP-1c knockout mice increased liver triglycerides, confirming the connection between CSE, autophagy, and SREBP-1c. Overall, our results uncover a 2-fold mechanism for SREBP-1c-driven hepatic lipid accumulation through reciprocal activation and inhibition of hepatic lipid biosynthesis and degradation, respectively.
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Sun Y, Huang S, Wan C, Ruan Q, Xie X, Wei D, Li G, Lin S, Li H, Wu S. Knockdown of lncRNA ENST00000609755.1 Confers Protection Against Early oxLDL-Induced Coronary Heart Disease. Front Cardiovasc Med 2021; 8:650212. [PMID: 34095248 PMCID: PMC8175657 DOI: 10.3389/fcvm.2021.650212] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/12/2021] [Indexed: 12/24/2022] Open
Abstract
Background: This study investigated the association between long non-coding RNAs (lncRNAs) and coronary heart disease (CHD) and further elucidated the potential biological roles of lncRNAs in CHD pathogenesis. Methods: A case-control study (590 patients and 590 controls) was conducted from February 2017 and March 2019 in Fuzhou, China. Environmental factors were investigated using questionnaires and physical examinations. Five representative lncRNAs were screened using lncRNA microarray (peripheral blood in 5 cases and 5 controls) and further verified by quantitative real-time polymerase chain reaction (peripheral blood leukocyte in 100 cases and 100 controls). Oxidized low-density lipoprotein (oxLDL) was used to induce a human coronary artery endothelial cell (HCAECs) injury model, and loss of function was used to elucidate the role of lncRNA ENST00000609755.1 (lnc-MICALL2-2) in oxLDL-induced HCAECs injury. Results: A total of 320 lncRNAs were found dysregulated in CHD patients (fold change> 2, p < 0.05). The results of a discovery microarray, population verification and HCAEC experiments suggested the lnc-MICALL2-2 is upregulated in CHD subjects and in an oxLDL-induced HCAECs injury model. Conversely, lnc-MICALL2-2 inhibition in vitro attenuated the effects of oxLDL on HCAECs morphology, proliferation, and apoptosis. Conclusion: Elevated expression of lnc-MICALL2-2 is an independent risk factor for CHD, and knockdown subsequently confers protection against early pathological processes of oxLDL-induced CHD.
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Affiliation(s)
- Yi Sun
- School of Public Health, Fujian Medical University, Fuzhou, China
| | - Shuna Huang
- Department of Clinical Research and Translation Center Office, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Chunyu Wan
- School of Public Health, Fujian Medical University, Fuzhou, China
| | - Qishuang Ruan
- Department of Orthopedics, Fujian Medical University Union Hospital, Fuzhou, China
| | - Xiaoxu Xie
- School of Public Health, Fujian Medical University, Fuzhou, China
| | - Donghong Wei
- School of Public Health, Fujian Medical University, Fuzhou, China
| | - Guobo Li
- School of Public Health, Fujian Medical University, Fuzhou, China
| | - Shaowei Lin
- School of Public Health, Fujian Medical University, Fuzhou, China
| | - Huangyuan Li
- School of Public Health, Fujian Medical University, Fuzhou, China
| | - Siying Wu
- School of Public Health, Fujian Medical University, Fuzhou, China
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Hu M, Jia F, Huang WP, Li X, Hu DF, Wang J, Ren KF, Fu GS, Wang YB, Ji J. Substrate stiffness differentially impacts autophagy of endothelial cells and smooth muscle cells. Bioact Mater 2021; 6:1413-1422. [PMID: 33210033 PMCID: PMC7658328 DOI: 10.1016/j.bioactmat.2020.10.013] [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: 09/26/2020] [Revised: 10/21/2020] [Accepted: 10/21/2020] [Indexed: 01/07/2023] Open
Abstract
Stiffening of blood vessels is one of the most important characteristics in the process of many cardiovascular pathologies such as atherosclerosis, angiosteosis, and vascular aging. Increased stiffness of the vascular extracellular matrix drives artery pathology and alters phenotypes of vascular cell. Understanding how substrate stiffness impacts vascular cell behaviors is of great importance to the biomaterial design in tissue engineering, regenerative medicine, and medical devices. Here we report that changing substrate stiffness has a significant impact on the autophagy of vascular endothelial cells (VECs) and smooth muscle cells (VSMCs). Interestingly, our findings demonstrate that, with the increase of substrate stiffness, the autophagy level of VECs and VSMCs showed differential changes: endothelial autophagy levels reduced, leading to the reductions in a range of gene expression associated with endothelial function; while, autophagy levels of VSMCs increased, showing a transition from contractile to the synthetic phenotype. We further demonstrate that, by inhibiting cell autophagy, the expressions of endothelial functional gene were further reduced and the expression of VSMC calponin increased, suggesting an important role of autophagy in response of the cells to the challenge of microenvironment stiffness changing. Although the underlying mechanism requires further study, this work highlights the relationship of substrate stiffness, autophagy, and vascular cell behaviors, and enlightening the design principles of surface stiffness of biomaterials in cardiovascular practical applications.
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Affiliation(s)
- Mi Hu
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Fan Jia
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Wei-Pin Huang
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Xu Li
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Deng-Feng Hu
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Jing Wang
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Ke-Feng Ren
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
| | - Guo-Sheng Fu
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
| | - Yun-Bing Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China
| | - Jian Ji
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China
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Verhoeven J, Baelen J, Agrawal M, Agostinis P. Endothelial cell autophagy in homeostasis and cancer. FEBS Lett 2021; 595:1497-1511. [PMID: 33837545 DOI: 10.1002/1873-3468.14087] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/19/2021] [Accepted: 03/22/2021] [Indexed: 01/01/2023]
Abstract
Autophagy, the major lysosomal pathway for the degradation and recycling of cytoplasmic materials, is increasingly recognized as a major player in endothelial cell (EC) biology and vascular pathology. Particularly in solid tumors, tumor microenvironmental stress such as hypoxia, nutrient deprivation, inflammatory mediators, and metabolic aberrations stimulates autophagy in tumor-associated blood vessels. Increased autophagy in ECs may serve as a mechanism to alleviate stress and restrict exacerbated inflammatory responses. However, increased autophagy in tumor-associated ECs can re-model metabolic pathways and affect the trafficking and surface availability of key mediators and regulators of the interplay between EC and immune cells. In line with this, heightened EC autophagy is involved in pathological angiogenesis, inflammatory, and immune responses. Here, we review major cellular and molecular mechanisms regulated by autophagy in ECs under physiological conditions and discuss recent evidence implicating EC autophagy in tumor angiogenesis and immunosurveillance.
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Affiliation(s)
- Jelle Verhoeven
- Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.,VIB Center for Cancer Biology Research, Leuven, Belgium
| | - Jef Baelen
- Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.,VIB Center for Cancer Biology Research, Leuven, Belgium
| | - Madhur Agrawal
- Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.,VIB Center for Cancer Biology Research, Leuven, Belgium
| | - Patrizia Agostinis
- Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.,VIB Center for Cancer Biology Research, Leuven, Belgium
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Alharbi YM, Bima AI, Elsamanoudy AZ. An Overview of the Perspective of Cellular Autophagy: Mechanism, Regulation, and the Role of Autophagy Dysregulation in the Pathogenesis of Diseases. J Microsc Ultrastruct 2021; 9:47-54. [PMID: 34350099 PMCID: PMC8291096 DOI: 10.4103/jmau.jmau_33_20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 05/22/2020] [Accepted: 05/29/2020] [Indexed: 11/22/2022] Open
Abstract
Autophagy is a cellular process that eliminates unnecessary cytoplasmic materials, such as long-age proteins, destroyed organelles, and foreign microorganisms. Macroautophagy (MaA), chaperone-mediated autophagy, and microautophagy are the three main types of autophagy. It is regulated by the integration of signaling from the AMPK and mTOR-ULK1 pathways. Autophagy plays a physiological role in health, and its dysregulation could be a pathophysiologic mechanism in different disease conditions. In the current study, we reviewed papers of Google Scholar database, PubMed, PubMed Central, Cochrane Database of Systematic Reviews, MEDLINE, and MedlinePlus with no time limitation and a recent World Health Organization report. In the current review, it could be concluded that autophagy plays many physiological functions, including immune system modulation, and regulates different cellular processes such as metabolism, protein synthesis, and cellular transportation. Dysregulation of autophagy is implicated in tumorigenesis, aging, age-related neurodegeneration, and endothelial dysfunctions. Autophagy dysregulation is also implicated in the newly discovered CoV-COVID-19 pathogenesis.
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Affiliation(s)
- Yasser M. Alharbi
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdulhadi I. Bima
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ayman Z. Elsamanoudy
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Sun CX, Zhu F, Qi L. Demethylated miR-216a Regulates High Mobility Group Box 3 Promoting Growth of Esophageal Cancer Cells Through Wnt/β-Catenin Pathway. Front Oncol 2021; 11:622073. [PMID: 33842327 PMCID: PMC8025835 DOI: 10.3389/fonc.2021.622073] [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: 10/27/2020] [Accepted: 03/03/2021] [Indexed: 12/15/2022] Open
Abstract
Background Esophageal cancer (EC) is the eighth most common cause of cancer-associated mortality in humans. Recent studies have revealed the important roles of microRNAs (miRs) in mediating tumor initiation and progression. miR-216a has been found to be involved in the progression of EC, but the underlying mechanisms remain largely unknown. The aim of this study is to explore the mechanism of miR-216a and the downstream molecules in esophageal cancer. Materials and Methods The degree of methylation of miR-216a promoter in EC tissues and cell lines was determined with methylation specific polymerase chain reaction (MSP). The levels of miR-216a and HMGB3 in EC cells were quantified by quantitative PCR (qPCR) and Western blot (WB). EC cell lines were treated with DNA methylation inhibitor 5-aza-2’-deoxycytidine (5-AZ), miR-216a mimics, and HMGB3 siRNA to explore the effects of miR-216a and HMGB3 on the proliferation, migration, invasion, and apoptosis of cells. Dual-luciferase reporter assay was employed to verify the binding of miR-216a to the 3’UTR of HMGB2 mRNA. Results The promoter of MiR-216a was hypermethylated and the expression of miR-216a was down-regulated in EC, while HMGB3 was up-regulated. Dual luciferase reporter assay confirmed the binding of miR-216a to the 3’UTR of HMGB3 mRNA. Demethylated miR-216a and miR-216a mimics elevated miR-216a expression and down-regulated HMGB3, as well as inhibited cell proliferation, migration, and invasion. Inhibiting the expression of HMGB3 played an important role in inducing apoptosis, suppressing cell expansion, and down-regulating the activity of Wnt/β-catenin pathway. Conclusions Hypermethylation in the promoter of miR-216a upregulated HMGB3 and the Wnt/β-catenin pathway, resulting in enhanced EC progression.
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Affiliation(s)
- Cheng-Xi Sun
- Department of Clinical Laboratory, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Feng Zhu
- Department of Thoracic Surgery, Shandong Provincial Chest Hospital, Jinan, China
| | - Lei Qi
- Department of Thoracic Surgery, Cheeloo College of Medicine, Shandong University, Jinan, China
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Carresi C, Mollace R, Macrì R, Scicchitano M, Bosco F, Scarano F, Coppoletta AR, Guarnieri L, Ruga S, Zito MC, Nucera S, Gliozzi M, Musolino V, Maiuolo J, Palma E, Mollace V. Oxidative Stress Triggers Defective Autophagy in Endothelial Cells: Role in Atherothrombosis Development. Antioxidants (Basel) 2021; 10:antiox10030387. [PMID: 33807637 PMCID: PMC8001288 DOI: 10.3390/antiox10030387] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 02/18/2021] [Accepted: 03/01/2021] [Indexed: 02/06/2023] Open
Abstract
Atherothrombosis, a multifactorial and multistep artery disorder, represents one of the main causes of morbidity and mortality worldwide. The development and progression of atherothrombosis is closely associated with age, gender and a complex relationship between unhealthy lifestyle habits and several genetic risk factors. The imbalance between oxidative stress and antioxidant defenses is the main biological event leading to the development of a pro-oxidant phenotype, triggering cellular and molecular mechanisms associated with the atherothrombotic process. The pathogenesis of atherosclerosis and its late thrombotic complications involve multiple cellular events such as inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells (SMCs), extracellular matrix (ECM) alterations, and platelet activation, contributing to chronic pathological remodeling of the vascular wall, atheromatous plague formation, vascular stenosis, and eventually, thrombus growth and propagation. Emerging studies suggest that clotting activation and endothelial cell (EC) dysfunction play key roles in the pathogenesis of atherothrombosis. Furthermore, a growing body of evidence indicates that defective autophagy is closely linked to the overproduction of reactive oxygen species (ROS) which, in turn, are involved in the development and progression of atherosclerotic disease. This topic represents a large field of study aimed at identifying new potential therapeutic targets. In this review, we focus on the major role played by the autophagic pathway induced by oxidative stress in the modulation of EC dysfunction as a background to understand its potential role in the development of atherothrombosis.
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Affiliation(s)
- Cristina Carresi
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
- Correspondence: ; Tel.: +39-09613694128; Fax: +39-09613695737
| | - Rocco Mollace
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Roberta Macrì
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Miriam Scicchitano
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Francesca Bosco
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Federica Scarano
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Anna Rita Coppoletta
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Lorenza Guarnieri
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Stefano Ruga
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Maria Caterina Zito
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Saverio Nucera
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Micaela Gliozzi
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Vincenzo Musolino
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Jessica Maiuolo
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Ernesto Palma
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
- Nutramed S.c.a.r.l., Complesso Ninì Barbieri, Roccelletta di Borgia, 88100 Catanzaro, Italy
| | - Vincenzo Mollace
- Research for Food Safety & Health IRC-FSH, Department of Health Sciences, University Magna Graecia, 88100 Catanzaro, Italy; (R.M.); (R.M.); (M.S.); (F.B.); (F.S.); (A.R.C.); (L.G.); (S.R.); (M.C.Z.); (S.N.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
- Nutramed S.c.a.r.l., Complesso Ninì Barbieri, Roccelletta di Borgia, 88100 Catanzaro, Italy
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Liao L, Yang Q, Li H, Meng R, Li Y. miR-454-3p prevents ox-LDL-induced apoptosis in HAECs by targeting TRPC3. Exp Ther Med 2021; 21:323. [PMID: 33732296 PMCID: PMC7905327 DOI: 10.3892/etm.2021.9754] [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: 11/28/2019] [Accepted: 07/29/2020] [Indexed: 12/18/2022] Open
Abstract
Endothelial-cell (EC) apoptosis serves a vital role in the pathogenesis of atherosclerosis. Accumulating evidence has implicated microRNA (miRNA/miR) dysregulation in EC apoptosis. Although the role of miR-454-3p in carcinogenesis has been well documented, its role and underlying mechanism in EC apoptosis remain unclear. In the present study, the results revealed that miR-454-3p expression was substantially downregulated in human aortic endothelial cells (HAECs) following oxidized low-density lipoprotein (ox-LDL) treatment. miR-454-3p suppression significantly attenuated the viability of HAECs, while miR-454-3p overexpression repressed ox-LDL-induced HAEC apoptosis. Bioinformatics analysis and luciferase reporter assays revealed that transient receptor potential canonical 3 (TRPC3), a key regulator of atherosclerosis development, was the direct target of miR-454-3p. Furthermore, TRPC3 overexpression abolished the anti-apoptotic effect of miR-454-3p on HAECs. These results revealed a novel role of miR-454-3p in ox-LDL-induced apoptosis in HAECs.
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Affiliation(s)
- Luming Liao
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China.,Department of Cardiovascular Internal Medicine, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Qiaolan Yang
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Hailiang Li
- Department of General Surgery, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Rongsen Meng
- Department of Cardiovascular Internal Medicine, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
| | - Yuntian Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China.,Department of Cardiovascular Internal Medicine, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong 510317, P.R. China
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42
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Autophagy in Acute Pancreatitis: Organelle Interaction and microRNA Regulation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8811935. [PMID: 33628384 PMCID: PMC7884169 DOI: 10.1155/2021/8811935] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/23/2020] [Accepted: 01/07/2021] [Indexed: 12/16/2022]
Abstract
Acute pancreatitis (AP) is a common disorder with significant hospital admission and mortality. Due to the unclarified pathological mechanism, there is still no effective and specific treatment for AP. Recently, autophagy has been found to be closely related with occurrence and development of AP, which is crucial in determining its severity and outcomes. Emerging evidence indicates that autophagy can be regulated and influenced by microRNAs and organelles, including mitochondria, endoplasmic reticulum and lysosome, through various ways in AP. Of note, the complex interplays and close relationships among autophagy, microRNA and organelles in AP are vital for figuring out pathogenesis but not clear yet. Thus, this review summarizes the role of autophagy in the pathological mechanism of AP, especially the relationship between impaired autophagy and organelles, and discusses the regulatory mechanism of microRNA on autophagy, which could offer new insights into understanding the pathogenesis of AP and developing new potential therapeutic targets against AP.
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43
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Jang JH, Lee TJ. The role of microRNAs in cell death pathways. Yeungnam Univ J Med 2021; 38:107-117. [PMID: 33435638 PMCID: PMC8016624 DOI: 10.12701/yujm.2020.00836] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 12/12/2020] [Indexed: 12/18/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of noncoding RNAs that negatively regulate target messenger RNAs. In multicellular eukaryotes, numerous miRNAs perform basic cellular functions, including cell proliferation, differentiation, and death. Abnormal expression of miRNAs weakens or modifies various apoptosis pathways, leading to the development of human cancer. Cell death occurs in an active manner that maintains tissue homeostasis and eliminates potentially harmful cells through regulated cell death processes, including apoptosis, autophagic cell death, and necroptosis. In this review, we discuss the involvement of miRNAs in regulating cell death pathways in cancers and the potential therapeutic functions of miRNAs in cancer treatment.
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Affiliation(s)
- Ji Hoon Jang
- Department of Anatomy, Yeungnam University College of Medicine, Daegu, Korea
| | - Tae-Jin Lee
- Department of Anatomy, Yeungnam University College of Medicine, Daegu, Korea
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44
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Giuliani A, Londin E, Ferracin M, Mensà E, Prattichizzo F, Ramini D, Marcheselli F, Recchioni R, Rippo MR, Bonafè M, Rigoutsos I, Olivieri F, Sabbatinelli J. Long-term exposure of human endothelial cells to metformin modulates miRNAs and isomiRs. Sci Rep 2020; 10:21782. [PMID: 33311640 PMCID: PMC7732983 DOI: 10.1038/s41598-020-78871-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 12/01/2020] [Indexed: 02/07/2023] Open
Abstract
Increasing evidence suggest that the glucose-lowering drug metformin exerts a valuable anti-senescence role. The ability of metformin to affect the biogenesis of selected microRNAs (miRNAs) was recently suggested. MicroRNA isoforms (isomiRs) are distinct variations of miRNA sequences, harboring addition or deletion of one or more nucleotides at the 5′ and/or 3′ ends of the canonical miRNA sequence. We performed a comprehensive analysis of miRNA and isomiR profile in human endothelial cells undergoing replicative senescence in presence of metformin. Metformin treatment was associated with the differential expression of 27 miRNAs (including miR-100-5p, -125b-5p, -654-3p, -217 and -216a-3p/5p). IsomiR analysis revealed that almost 40% of the total miRNA pool was composed by non-canonical sequences. Metformin significantly affects the relative abundance of 133 isomiRs, including the non-canonical forms of the aforementioned miRNAs. Pathway enrichment analysis suggested that pathways associated with proliferation and nutrient sensing are modulated by metformin-regulated miRNAs and that some of the regulated isomiRs (e.g. the 5′ miR-217 isomiR) are endowed with alternative seed sequences and share less than half of the predicted targets with the canonical form. Our results show that metformin reshapes the senescence-associated miRNA/isomiR patterns of endothelial cells, thus expanding our insight into the cell senescence molecular machinery.
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Affiliation(s)
- Angelica Giuliani
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | - Eric Londin
- Computational Medicine Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Manuela Ferracin
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Emanuela Mensà
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | | | - Deborah Ramini
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | | | - Rina Recchioni
- Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA, Ancona, Italy
| | - Maria Rita Rippo
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
| | - Massimiliano Bonafè
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Isidore Rigoutsos
- Computational Medicine Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Via Tronto 10/A, 60126, Ancona, Italy. .,Center of Clinical Pathology and Innovative Therapy, IRCCS INRCA, Ancona, Italy.
| | - Jacopo Sabbatinelli
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Via Tronto 10/A, 60126, Ancona, Italy
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45
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Florio MC, Magenta A, Beji S, Lakatta EG, Capogrossi MC. Aging, MicroRNAs, and Heart Failure. Curr Probl Cardiol 2020; 45:100406. [PMID: 30704792 PMCID: PMC10544917 DOI: 10.1016/j.cpcardiol.2018.12.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Accepted: 12/23/2018] [Indexed: 12/12/2022]
Abstract
Aging is a major risk factor for heart failure, one of the leading causes of death in Western society. The mechanisms that underlie the different forms of heart failure have been elucidated only in part and the role of noncoding RNAs is still poorly characterized. Specifically, microRNAs (miRNAs), a class of small noncoding RNAs that can modulate gene expression at the posttranscriptional level in all cells, including myocardial and vascular cells, have been shown to play a role in heart failure with reduced ejection fraction. In contrast, miRNAs role in heart failure with preserved ejection fraction, the predominant form of heart failure in the elderly, is still unknown. In this review, we will focus on age-dependent miRNAs in heart failure and on some other conditions that are prevalent in the elderly and are frequently associated with heart failure with preserved ejection fraction.
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MicroRNA-216a Promotes Endothelial Inflammation by Smad7/I κB α Pathway in Atherosclerosis. DISEASE MARKERS 2020; 2020:8864322. [PMID: 33282009 PMCID: PMC7688351 DOI: 10.1155/2020/8864322] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 10/14/2020] [Accepted: 10/28/2020] [Indexed: 01/23/2023]
Abstract
Background The endothelium is the first line of defence against harmful microenvironment risks, and microRNAs (miRNAs) involved in vascular inflammation may be promising therapeutic targets to modulate atherosclerosis progression. In this study, we aimed to investigate the mechanism by which microRNA-216a (miR-216a) modulated inflammation activation of endothelial cells. Methods. A replicative senescence model of human umbilical vein endothelial cells (HUVECs) was established, and population-doubling levels (PDLs) were defined during passages. PDL8 HUVECs were transfected with miR-216a mimics/inhibitor or small interfering RNA (siRNA) of SMAD family member 7 (Smad7). Real-time PCR and Western blot assays were performed to detect the regulatory role of miR-216a on Smad7 and NF-κB inhibitor alpha (IκBα) expression. The effect of miR-216a on adhesive capability of HUVECs to THP-1 cells was examined. MiR-216a and Smad7 expression in vivo were measured using human carotid atherosclerotic plaques of the patients who underwent carotid endarterectomy (n = 41). Results Luciferase assays showed that Smad7 was a direct target of miR-216a. Smad7 mRNA expression, negatively correlated with miR-216a during endothelial aging, was downregulated in senescent PDL44 cells, compared with young PDL8 HUVECs. MiR-216a markedly increased endothelial inflammation and adhesive capability to monocytes in PDL8 cells by promoting the phosphorylation and degradation of IκBα and then activating NF-κB signalling pathway. The effect of miR-216a on endothelial cells was consistent with that blocked Smad7 by siRNAs. When inhibiting endogenous miR-216a, the Smad7/IκBα expression was rescued, which led to decreased endothelial inflammation and monocytes recruitment. In human carotid atherosclerotic plaques, Smad7 level was remarkably decreased in high miR-216a group compared with low miR-216a group. Moreover, miR-216a was negatively correlated with Smad7 and IκBα levels and positively correlated with interleukin 1 beta (IL1β) expression in vivo. Conclusion In summary, our findings suggest a new mechanism of vascular endothelial inflammation involving Smad7/IκBα signalling pathway in atherosclerosis.
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Gao J, Chen X, Shan C, Wang Y, Li P, Shao K. Autophagy in cardiovascular diseases: role of noncoding RNAs. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 23:101-118. [PMID: 33335796 PMCID: PMC7732971 DOI: 10.1016/j.omtn.2020.10.039] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cardiovascular diseases (CVDs) remain the world's leading cause of death. Cardiomyocyte autophagy helps maintain normal metabolism and functioning of the heart. Importantly, mounting evidence has revealed that autophagy plays a dual role in CVD pathology. Under physiological conditions, moderate autophagy maintains cell metabolic balance by degrading and recycling damaged organelles and proteins, and it promotes myocardial survival, but excessive or insufficient autophagy is equally deleterious and contributes to disease progression. Noncoding RNAs (ncRNAs) are a class of RNAs transcribed from the genome, but most ncRNAs do not code for functional proteins. In recent years, increasingly, various ncRNAs have been identified, and they play important regulatory roles in the physiological and pathological processes of organisms, as well as in autophagy. Thus, determining whether ncRNA-regulated autophagy plays a protective role in CVDs or promotes their progression can help us to develop ncRNAs as therapeutic targets in autophagy-related CVDs. In this review, we briefly summarize the regulatory roles of several important ncRNAs, including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), in the autophagy of various CVDs to provide a theoretical basis for the etiology and pathogenesis of CVDs and develop novel therapies to treat CVDs.
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Affiliation(s)
- Jinning Gao
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Xiatian Chen
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Chan Shan
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yin Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Kai Shao
- Department of Central Laboratory, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, 758 Hefei Road, Qingdao, Shandong 266035, China
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Liang S, Hu J, Zhang A, Li F, Li X. miR-155 induces endothelial cell apoptosis and inflammatory response in atherosclerosis by regulating Bmal1. Exp Ther Med 2020; 20:128. [PMID: 33082860 PMCID: PMC7557345 DOI: 10.3892/etm.2020.9259] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 06/18/2020] [Indexed: 12/12/2022] Open
Abstract
Atherosclerosis is the leading cause of death from vascular diseases worldwide, and endothelial cell (EC) dysfunction is the key cause of atherosclerosis. miR-155 was found to induce endothelial injury and to trigger atherosclerosis. In addition, brain and muscle ARNT-like protein-1 (Bmal1) has been found to be closely related to EC function. Therefore, the present study aimed to explore the mechanism underlying the regulation of Bmal1 by miR-155 in the induction of EC apoptosis and inflammatory response in atherosclerosis. The atherosclerosis model in apolipoprotein E (ApoE)- / - mice was established. miR-155 and Bmal1 expression was quantified by RT-qPCR and western blot analysis, respectively. The role of miR-155 and Bmal1 in atherosclerosis was evaluated through changes in cardiac function, plaque area, cardiomyocyte apoptosis, and inflammatory factor levels in mice. Moreover, the regulatory relationship between them was identified by dual-luciferase reporter gene assay to explore the mechanism of action of miR-155. After the modeling, the expression of miR-155 was upregulated and Bmal1 was downregulated in aorta, and there was a significant linear correlation between them. Upregulation of miR-155 increased the atherosclerotic plaque area, cell apoptosis, total cholesterol (TC) and triglyceride (TG), as well as weakened aortic diastolic function. However, opposite changes occurred after downregulation of miR-155 or an increase in Bmal1. In addition, the microRNA.org website predicted that there were targeted binding sites between miR-155 and Bmal1, which was verified with a dual-luciferase reporter gene assay. miR-155 was able to inhibit the expression by targeting Bmal1. Moreover, a rescue experiment showed that Bmal1 hindered the promotion of miR-155 in regards to atherosclerosis. In conclusion, miR-155 induces EC apoptosis and inflammatory response, weakens aortic diastolic function, and promotes the progression of atherosclerosis through targeted inhibition of Bmal1.
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Affiliation(s)
- Shuangchao Liang
- Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China.,Department of Vascular Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Jiqiong Hu
- Department of Vascular Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Andong Zhang
- Department of Vascular Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Fangkuan Li
- Department of Vascular Surgery, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241000, P.R. China
| | - Xiaoqiang Li
- Department of Vascular Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
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49
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Ait-Aissa K, Nguyen QM, Gabani M, Kassan A, Kumar S, Choi SK, Gonzalez AA, Khataei T, Sahyoun AM, Chen C, Kassan M. MicroRNAs and obesity-induced endothelial dysfunction: key paradigms in molecular therapy. Cardiovasc Diabetol 2020; 19:136. [PMID: 32907629 PMCID: PMC7488343 DOI: 10.1186/s12933-020-01107-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 08/28/2020] [Indexed: 01/17/2023] Open
Abstract
The endothelium plays a pivotal role in maintaining vascular health. Obesity is a global epidemic that has seen dramatic increases in both adult and pediatric populations. Obesity perturbs the integrity of normal endothelium, leading to endothelial dysfunction which predisposes the patient to cardiovascular diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that play important roles in a variety of cellular processes such as differentiation, proliferation, apoptosis, and stress response; their alteration contributes to the development of many pathologies including obesity. Mediators of obesity-induced endothelial dysfunction include altered endothelial nitric oxide synthase (eNOS), Sirtuin 1 (SIRT1), oxidative stress, autophagy machinery and endoplasmic reticulum (ER) stress. All of these factors have been shown to be either directly or indirectly caused by gene regulatory mechanisms of miRNAs. In this review, we aim to provide a comprehensive description of the therapeutic potential of miRNAs to treat obesity-induced endothelial dysfunction. This may lead to the identification of new targets for interventions that may prevent or delay the development of obesity-related cardiovascular disease.
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Affiliation(s)
- Karima Ait-Aissa
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
| | - Quynh My Nguyen
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, USA
| | - Mohanad Gabani
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Adam Kassan
- Department of Pharmaceutical Sciences, School of Pharmacy, West Coast University, Los Angeles, USA
| | - Santosh Kumar
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Soo-Kyoung Choi
- Department of Physiology, College of Medicine, Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, South Korea
| | - Alexis A Gonzalez
- Instituto de Química, Pontificia, Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Tahsin Khataei
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Amal M Sahyoun
- Department of Food Science and Agriculture Chemistry, McGill University, Montreal, QC, Canada
| | - Cheng Chen
- Department of emergency and Critical Care, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Modar Kassan
- Cardiovascular Division, Department of Medicine, and Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
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50
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Vonhögen IGC, Mohseni Z, Winkens B, Xiao K, Thum T, Calore M, da Costa Martins PA, de Windt LJ, Spaanderman MEA, Ghossein-Doha C. Circulating miR-216a as a biomarker of metabolic alterations and obesity in women. Noncoding RNA Res 2020; 5:144-152. [PMID: 32954093 PMCID: PMC7479169 DOI: 10.1016/j.ncrna.2020.08.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 08/18/2020] [Accepted: 08/18/2020] [Indexed: 12/23/2022] Open
Abstract
Obesity leads to an amplified risk of disease and contributes to the occurrence of type 2 diabetes, fatty liver disease, coronary heart disease, stroke, chronic kidney disease and various types of cancer. MicroRNAs (miRNAs), small non-coding RNA molecules of 20-25 nucleotides, can remain stable in plasma and have been studied as potential (predictive) biomarkers for obesity and related metabolic disorders. The aim of this study was to identify circulating miRNAs as biomarkers for obesity status and metabolic alterations in women. Circulating miR-216a and miR-155-5p were selected by miRNA expression profiling and validated by real time quantitative PCR in a validation cohort of 60 obese women and 60 normal weight-age-matched control women. This was supplemented by correlation analysis of the candidate miRNA and anthropometric variables, blood biochemistry and lipid profile markers. Circulating miR-216a was validated as a biomarker of obesity status with significantly reduced levels in obese women. Interestingly, this was associated with a negative correlation between the plasma miR-216a content and body mass index (BMI), waist circumference, mean arterial pressure (MAP), triglycerides, ratio of total cholesterol/high density lipoprotein (HDL)-cholesterol and high sensitivity-C reactive protein (hs-CRP).Taken together, we provide evidence for an abnormally expressed circulating miRNA, miR-216a, with additive value as a predictive marker for obesity that correlates with metabolic alterations presented by lipid profile and inflammatory markers.
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Affiliation(s)
- Indira G C Vonhögen
- Department of Molecular Genetics (DMG), Faculty of Science and Engineering; CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Zenab Mohseni
- Department of Molecular Genetics (DMG), Faculty of Science and Engineering; CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Bjorn Winkens
- Department of Methodology and Statistics, Care and Public Health Research Institute (CAPHRI), Faculty of Health, Medicine and Life Sciences, Maastricht University, the Netherlands
| | - Ke Xiao
- Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany
| | - Thomas Thum
- Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Germany
| | - Martina Calore
- Department of Molecular Genetics (DMG), Faculty of Science and Engineering; CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Paula A da Costa Martins
- Department of Molecular Genetics (DMG), Faculty of Science and Engineering; CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Leon J de Windt
- Department of Molecular Genetics (DMG), Faculty of Science and Engineering; CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Marc E A Spaanderman
- Department of Obstetrics and Gynecology, School for Oncology & Developmental Biology (GROW), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre (MUMC+), the Netherlands
| | - Chahinda Ghossein-Doha
- Department of Obstetrics and Gynecology, School for Oncology & Developmental Biology (GROW), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre (MUMC+), the Netherlands
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