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1
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Huang X, Li Y, Li J, Jiang Y, Cui W, Zhou H, Tang L. The long noncoding RNA loc107053557 acts as a gga-miR-3530-5p sponge to suppress the replication of vvIBDV through regulating STAT1 expression. Virulence 2024; 15:2333237. [PMID: 38528779 PMCID: PMC10984138 DOI: 10.1080/21505594.2024.2333237] [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: 10/18/2023] [Accepted: 03/16/2024] [Indexed: 03/27/2024] Open
Abstract
Infectious bursal disease virus (IBDV) causes immunosuppression and high mortality in young chickens. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are important regulators during viral infection. However, detailed the regulatory mechanisms of lncRNA-miRNA-mRNA have not yet been described in IBDV infection. Here, we analysed the role of lncRNA53557/gga-miR-3530-5p/STAT1 axis in very virulent IBDV (vvIBDV) infection. Evidently upregulated expression of lncRNA53557 was observed in bursa of Fabricius and DT40 cells. Meanwhile, overexpression of lncRNA53557 promoted STAT1 expression and inhibited vvIBDV replication and vice versa, indicating that the upregulation of lncRNA53557 was part of the host antiviral defence. The subcellular fractionation assay confirmed that lncRNA53557 can be localized in the cytoplasm. Further, dual-luciferase reporter, RNA pulldown, FISH and RT-qPCR assays revealed that lncRNA53557 were directly bound to gga-miR-3530-5p and had a negative regulatory relationship between them. Subsequent mechanistic analysis showed that lncRNA53557 acted as a competing endogenous RNA (ceRNA) of gga-miR-3530-5p to relieve the repressive effect of gga-miR-3530-5p on its target STAT1, as well as Mx1, OASL, and ISG15, thereby suppressing vvIBDV replication. The study reveals that a network of enriched lncRNAs and lncRNA-associated ceRNA is involved in the regulation of IBDV infection, offering new insight into the mechanisms underlying IBDV-host interaction.
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Affiliation(s)
- Xuewei Huang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, P.R. China
| | - Yue Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Jiaxuan Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Yanping Jiang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, P.R. China
| | - Wen Cui
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, P.R. China
| | - Han Zhou
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, P.R. China
| | - Lijie Tang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, P.R. China
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2
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Genome-wide identification of chicken bursae of Fabricius miRNAs in response to very virulent infectious bursal disease virus. Arch Virol 2022; 167:1855-1864. [PMID: 35752686 DOI: 10.1007/s00705-022-05496-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 04/19/2022] [Indexed: 11/02/2022]
Abstract
Infectious bursal disease virus (IBDV) can cause a highly contagious immunosuppressive disease in young chickens. MicroRNAs (miRNAs) are crucial regulators of gene expression and are involved in the pathogenesis of IBDV infection. To investigate the roles of miRNA in chicken bursae of Fabricius in response to very virulent IBDV (vvIBDV) infection, RNA sequencing was performed to compare the small RNA libraries from uninfected and vvIBDV-infected group which was infected for 3 days. A total of 77 differentially expressed (DE) miRNAs were identified in BF, of which 42 DE miRNAs were upregulated and 35 DE miRNAs were downregulated. A gene ontology analysis showed that genes associated with cellular processes, cells, and binding were enriched. Moreover, pathway analyses suggested that apoptosis, T cell receptor signaling pathways, and chemokine signaling pathways may be activated following vvIBDV infection. In addition, we predicted the target genes of DE miRNAs and constructed an miRNA-mRNA regulatory network. In total, 189 pairs of miRNA-target genes were identified, comprising 67 DE miRNAs and 73 mRNAs. In this network, gga-miR-1684b-3p was identified with the highest fold change, as well as gga-miR-1788-3p and gga-miR-3530-5p showed a high degree of change. The above three miRNAs were considered to play vital roles in vvIBDV-host interactions. This study was the first to perform a comprehensive analysis of DE miRNAs in the bursa of Fabricius in response to vvIBDV infection, and it provided new insights into molecular mechanisms underlying vvIBDV infection and pathogenesis.
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3
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Luo F, Liu W, Bu H. MicroRNAs in hypertrophic cardiomyopathy: pathogenesis, diagnosis, treatment potential and roles as clinical biomarkers. Heart Fail Rev 2022; 27:2211-2221. [PMID: 35332416 DOI: 10.1007/s10741-022-10231-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/15/2022] [Indexed: 12/28/2022]
Abstract
Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy and is characterized by increased left ventricular wall thickness, but existing diagnostic and treatment approaches face limitations. MicroRNAs (miRNAs) are type of noncoding RNA molecule that plays crucial roles in the pathological process of cardiac remodelling. Accordingly, miRNAs related to HCM may represent potential novel therapeutic targets. In this review, we first discuss the different roles of miRNAs in the development of HCM. We then summarize the roles of common miRNAs as diagnostic and clinical biomarkers in HCM. Finally, we outline current and future challenges and potential new directions for miRNA-based therapeutics for HCM.
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Affiliation(s)
- Fanyan Luo
- The Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China.,National Clinical Research Centre for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Liu
- The Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China.,National Clinical Research Centre for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Haisong Bu
- The Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People's Republic of China. .,National Clinical Research Centre for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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4
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Zhou H, Tang W, Yang J, Peng J, Guo J, Fan C. MicroRNA-Related Strategies to Improve Cardiac Function in Heart Failure. Front Cardiovasc Med 2021; 8:773083. [PMID: 34869689 PMCID: PMC8639862 DOI: 10.3389/fcvm.2021.773083] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 10/25/2021] [Indexed: 12/18/2022] Open
Abstract
Heart failure (HF) describes a group of manifestations caused by the failure of heart function as a pump that supports blood flow through the body. MicroRNAs (miRNAs), as one type of non-coding RNA molecule, have crucial roles in the etiology of HF. Accordingly, miRNAs related to HF may represent potential novel therapeutic targets. In this review, we first discuss the different roles of miRNAs in the development and diseases of the heart. We then outline commonly used miRNA chemical modifications and delivery systems. Further, we summarize the opportunities and challenges for HF-related miRNA therapeutics targets, and discuss the first clinical trial of an antisense drug (CDR132L) in patients with HF. Finally, we outline current and future challenges and potential new directions for miRNA-based therapeutics for HF.
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Affiliation(s)
- Huatao Zhou
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Weijie Tang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jinfu Yang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
- Department of Pharmacology, Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Jun Peng
- Department of Pharmacology, Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Jianjun Guo
- Hunan Fangsheng Pharmaceutical Co., Ltd. Changsha, China
| | - Chengming Fan
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
- Department of Pharmacology, Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
- Hunan Fangsheng Pharmaceutical Co., Ltd. Changsha, China
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5
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Bär C, Chatterjee S, Falcão Pires I, Rodrigues P, Sluijter JPG, Boon RA, Nevado RM, Andrés V, Sansonetti M, de Windt L, Ciccarelli M, Hamdani N, Heymans S, Figuinha Videira R, Tocchetti CG, Giacca M, Zacchigna S, Engelhardt S, Dimmeler S, Madonna R, Thum T. Non-coding RNAs: update on mechanisms and therapeutic targets from the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart. Cardiovasc Res 2021; 116:1805-1819. [PMID: 32638021 DOI: 10.1093/cvr/cvaa195] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/15/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023] Open
Abstract
Vast parts of mammalian genomes are actively transcribed, predominantly giving rise to non-coding RNA (ncRNA) transcripts including microRNAs, long ncRNAs, and circular RNAs among others. Contrary to previous opinions that most of these RNAs are non-functional molecules, they are now recognized as critical regulators of many physiological and pathological processes including those of the cardiovascular system. The discovery of functional ncRNAs has opened up new research avenues aiming at understanding ncRNA-related disease mechanisms as well as exploiting them as novel therapeutics in cardiovascular therapy. In this review, we give an update on the current progress in ncRNA research, particularly focusing on cardiovascular physiological and disease processes, which are under current investigation at the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart. This includes a range of topics such as extracellular vesicle-mediated communication, neurohormonal regulation, inflammation, cardiac remodelling, cardio-oncology as well as cardiac development and regeneration, collectively highlighting the wide-spread involvement and importance of ncRNAs in the cardiovascular system.
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Affiliation(s)
- Christian Bär
- Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.,REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Shambhabi Chatterjee
- Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.,REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Inês Falcão Pires
- Cardiovascular Research and Development Center, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Patrícia Rodrigues
- Cardiovascular Research and Development Center, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Joost P G Sluijter
- Experimental Cardiology Laboratory, UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
| | - Reinier A Boon
- Department of Physiology, Amsterdam Cardiovascular Sciences (ACS), Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands.,Institute for Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany.,Partner site Rhein/Main, German Center for Cardiovascular Research (DZHK), Frankfurt am Main, Germany
| | - Rosa M Nevado
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Vicente Andrés
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Marida Sansonetti
- Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.,REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.,Department of Molecular Genetics, Faculty of Science and Engineering, Maastricht University, Maastricht, The Netherlands.,Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Leon de Windt
- Department of Molecular Genetics, Faculty of Science and Engineering, Maastricht University, Maastricht, The Netherlands.,Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Italy
| | - Nazha Hamdani
- Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Stephane Heymans
- Department of Cardiology, Maastricht University Medical Centre, University Hospital Maastricht, The Netherlands.,Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), University Hospital Maastricht, The Netherlands
| | - Raquel Figuinha Videira
- Cardiovascular Research and Development Center, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Molecular Genetics, Faculty of Science and Engineering, Maastricht University, Maastricht, The Netherlands.,Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Carlo G Tocchetti
- Department of Translational Medical Sciences and Interdepartmental Center of Clinical and Translational Research (CIRCET), Federico II University, Naples, Italy
| | - Mauro Giacca
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.,School of Cardiovascular Medicine & Sciences, King's College London, London, UK.,Department of Medicine, Surgery and Health Sciences, University of Trieste, Italy
| | - Serena Zacchigna
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.,Department of Medicine, Surgery and Health Sciences, University of Trieste, Italy
| | - Stefan Engelhardt
- Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Str. 29, Munich 80802, Germany.,DZHK (German Center for Cardiovascular Research), Partner site Munich Heart Alliance, Biedersteiner Str. 29, Munich 80802, Germany
| | - Stefanie Dimmeler
- Institute for Cardiovascular Regeneration, Goethe University, Germany.,German Center for Cardiovascular Research (DZHK), Frankfurt, Germany.,Cardio-Pulmonary Institute (CPI), Frankfurt, Germany
| | - Rosalinda Madonna
- Institute of Cardiology, University of Pisa, Pisa, Italy.,Department of Internal Medicine, University of Texas Medical School, Houston, TX, USA
| | - Thomas Thum
- Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.,REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
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6
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Su D, Meng Y. Biological effects of miRNA-24/E2F1 on myocardial ischemia-reperfusion injury. Minerva Surg 2021; 77:187-188. [PMID: 34342400 DOI: 10.23736/s2724-5691.21.09030-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Dexing Su
- Department of Cardiology, Zhangqiu District people's Hospital, Jinan, China
| | - Yan Meng
- Department of Cardiology, Zhangqiu District people's Hospital, Jinan, China -
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7
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Long Noncoding RNA XIST/miR-17/PTEN Axis Modulates the Proliferation and Apoptosis of Vascular Smooth Muscle Cells to Affect Stanford Type A Aortic Dissection. J Cardiovasc Pharmacol 2021; 76:53-62. [PMID: 32282501 DOI: 10.1097/fjc.0000000000000835] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Stanford type A aortic dissection (TAAD) is one of the most lethal cardiovascular diseases with an extremely high morbidity and mortality rate. LncRNA X-inactive specific transcript (XIST) is abundantly expressed in human thoracic aortic dissection, indicating it may play important roles in TAAD progression. However, the molecular mechanism of lncRNA XIST in TAAD is still in its infancy. Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of XIST and miR-17 in the aortic wall tissues of TAAD patients and age-matched healthy volunteers. The relationships between XIST, miR-17, and PTEN were evaluated using dual-luciferase reporter, western blot, and qRT-PCR assays. The biological functions of XIST in rat aortic vascular smooth muscle cells (VSMCs) were explored with Cell Counting Kit 8 (CCK-8), qRT-PCR, and western blot assays. Results found that XIST was upregulated in aortic wall tissues of patients with TAAD and associated with the prognosis of patients with TAAD. Silence XIST facilitated VSMC proliferation and inhibited VSMC apoptosis, whereas restoration XIST displayed opposite effects. Moreover, mechanistic studies revealed that XIST contained binding sites for miR-17 and miR-17 downregulation reversed the elevation of cell proliferation and attenuation of cell apoptosis, which was induced by silence XIST. Further study revealed that XIST positively regulated PTEN expression through its competitive target miR-17. In conclusion, knockdown of lncRNA XIST might attenuate the progression of TAAD by sponging miR-17 and regulating the following downstream PTEN, which suggested a novel therapeutic target for TAAD treatment.
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8
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Hosen MR, Goody PR, Zietzer A, Nickenig G, Jansen F. MicroRNAs As Master Regulators of Atherosclerosis: From Pathogenesis to Novel Therapeutic Options. Antioxid Redox Signal 2020; 33:621-644. [PMID: 32408755 DOI: 10.1089/ars.2020.8107] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Significance: Cardiovascular disease (CVD) remains the major cause of morbidity and mortality worldwide. Accumulating evidence indicates that atherosclerosis and its sequelae, coronary artery disease, contribute to the majority of cardiovascular deaths. Atherosclerosis is a chronic inflammatory disease of the arteries in which atherosclerotic plaques form within the vessel wall. Epidemiological studies have identified various risk factors for atherosclerosis, such as diabetes, hyperlipidemia, smoking, genetic predisposition, and sedentary lifestyle. Recent Advances: Through the advancement of genetic manipulation techniques and their use in cardiovascular biology, it was shown that small RNAs, especially microRNAs (miRNAs), are dynamic regulators of disease pathogenesis. They are considered to be central during the regulation of gene expression through numerous mechanisms and provide a means to develop biomarkers and therapeutic tools for the diagnosis and therapy of atherosclerosis. Circulating miRNAs encapsulated within membrane-surrounded vesicles, which originate from diverse subcellular compartments, are now emerging as novel regulators of intercellular communication. The miRNAs, in both freely circulating and vesicle-bound forms, represent a valuable tool for diagnosing and monitoring CVD, recently termed as "liquid biopsy." Critical Issues: However, despite the recent advancements in miRNA-based diagnostics and therapeutics, understanding how miRNAs can regulate atherosclerosis is still crucial to achieving an effective intervention and reducing the disease burden. Future Directions: We provide a landscape of the current developmental progression of RNA therapeutics as a holistic approach for treating CVD in different animal models and clinical trials. Future interrogations are warranted for the development of miRNA-based therapeutics to overcome challenges for the treatment of the disease.
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Affiliation(s)
- Mohammed Rabiul Hosen
- Department of Internal Medicine II, Molecular Cardiology, Heart Center Bonn, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany
| | - Philip Roger Goody
- Department of Internal Medicine II, Molecular Cardiology, Heart Center Bonn, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany
| | - Andreas Zietzer
- Department of Internal Medicine II, Molecular Cardiology, Heart Center Bonn, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany
| | - Georg Nickenig
- Department of Internal Medicine II, Molecular Cardiology, Heart Center Bonn, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany
| | - Felix Jansen
- Department of Internal Medicine II, Molecular Cardiology, Heart Center Bonn, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany
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9
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Tian D, Xiang Y, Tang Y, Ge Z, Li Q, Zhang Y. Circ-ADAM9 targeting PTEN and ATG7 promotes autophagy and apoptosis of diabetic endothelial progenitor cells by sponging mir-20a-5p. Cell Death Dis 2020; 11:526. [PMID: 32661238 PMCID: PMC7359341 DOI: 10.1038/s41419-020-02745-x] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 06/16/2020] [Accepted: 07/02/2020] [Indexed: 02/06/2023]
Abstract
Dysfunction of endothelial progenitor cells (EPCs) is a key factor in vascular complications of diabetes mellitus. Although the roles of microRNAs and circular RNAs in regulating cell functions have been thoroughly studied, their role in regulating autophagy and apoptosis of EPCs remains to be elucidated. This study investigated the roles of mir-20a-5p and its predicted target circ-ADAM9 in EPCs treated with high glucose (30 mM) and in a diabetic mouse hind limb ischemia model. It is found that Mir-20a-5p inhibited autophagy and apoptosis of EPCs induced by high-concentration glucose. Further, mir-20a-5p could inhibit the expression of PTEN and ATG7 in EPCs, and promote the phosphorylation of AKT and mTOR proteins under high-glucose condition. Investigation of the underlying mechanism revealed that circ-ADAM9, as a miRNA sponges of mir-20a-5p, promoted autophagy and apoptosis of EPCs induced by high-concentration glucose. Circ-ADAM9 upregulated PTEN and ATG7 in interaction with mir-20a-5p, and inhibited the phosphorylation of AKT and mTOR to aggravate autophagy and apoptosis of EPCs under high glucose. In addition, silencing of circ-ADAM9 increased microvessel formation in the hind limbs of diabetic mice. Our findings disclose a novel autophagy/apoptosis-regulatory pathway that is composed of mir-20a-5p, circ-ADAM9, PTEN, and ATG7. Circ-ADAM9 is a potential novel target for regulating the function of diabetic EPCs and angiogenesis.
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Affiliation(s)
- Ding Tian
- Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yin Xiang
- Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yong Tang
- Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhuowang Ge
- Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qianhui Li
- Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yachen Zhang
- Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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10
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Luo M, Sun Q, Zhao H, Tao J, Yan D. Long noncoding RNA NEAT1 sponges miR‐495‐3p to enhance myocardial ischemia‐reperfusion injury via MAPK6 activation. J Cell Physiol 2019; 235:105-113. [PMID: 31347173 DOI: 10.1002/jcp.28791] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 04/21/2019] [Accepted: 04/24/2019] [Indexed: 01/03/2023]
Affiliation(s)
- Man Luo
- Department of Emergency The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University Huai'an Jiangsu China
| | - Qingsong Sun
- Department of Emergency The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University Huai'an Jiangsu China
| | - Hongmei Zhao
- Department of Emergency The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University Huai'an Jiangsu China
| | - Jiali Tao
- Department of Emergency The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University Huai'an Jiangsu China
| | - Dongsheng Yan
- Department of Gastroenterological Surgery The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University Huai'an Jiangsu China
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11
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Mitochondrial miR-762 regulates apoptosis and myocardial infarction by impairing ND2. Cell Death Dis 2019; 10:500. [PMID: 31235686 PMCID: PMC6591419 DOI: 10.1038/s41419-019-1734-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 05/01/2019] [Accepted: 05/28/2019] [Indexed: 12/11/2022]
Abstract
Mitochondrial dysfunction plays a major role in the pathogenesis of cardiovascular diseases. MicroRNAs (miRNAs) are small RNAs that act as negative regulators of gene expression, but how miRNAs affect mitochondrial function in the heart is unclear. Using a miRNA microarray assay, we found that miR-762 predominantly translocated in the mitochondria and was significantly upregulated upon anoxia/reoxygenation (A/R) treatment. Knockdown of endogenous miR-762 significantly attenuated the decrease in intracellular ATP levels, the increase in ROS levels, the decrease in mitochondrial complex I enzyme activity and the increase in apoptotic cell death in cardiomyocytes, which was induced by A/R treatment. In addition, knockdown of miR-762 ameliorated myocardial ischemia/reperfusion (I/R) injury in mice. Mechanistically, we showed that enforced expression of miR-762 dramatically decreased the protein levels of endogenous NADH dehydrogenase subunit 2 (ND2) but had no effect on the transcript levels of ND2. The luciferase reporter assay showed that miR-762 bound to the coding sequence of ND2. In addition, knockdown of endogenous ND2 significantly decreased intracellular ATP levels, increased ROS levels, reduced mitochondrial complex I enzyme activity and increased apoptotic cell death in cardiomyocytes, which was induced by A/R treatment. Furthermore, we found that the inhibitory effect of miR-762 downregulation was attenuated by ND2 knockdown. Thus, our findings suggest that miR-762 participates in the regulation of mitochondrial function and cardiomyocyte apoptosis by ND2, a core assembly subunit of mitochondrial complex I. Our results revealed that mitochondrial miR-762, as a new player in mitochondrial dysfunction, may provide a new therapeutic target for myocardial infarction.
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12
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Fung EC, Butt AN, Eastwood J, Swaminathan R, Sodi R. Circulating microRNA in cardiovascular disease. Adv Clin Chem 2019; 91:99-122. [PMID: 31331491 DOI: 10.1016/bs.acc.2019.03.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Acute myocardial infarction (AMI) and heart failure (HF) are two major causes of cardiovascular mortality and morbidity. Early diagnosis of these conditions is essential to instigate immediate treatment that may result in improved outcomes. Traditional biomarkers of AMI include cardiac troponins and other proteins released from the injured myocardium but there are a number of limitations with these biomarkers especially with regard to specificity. In the past few years circulating nucleic acids, notably microRNA that are small non-coding RNAs that regulate various cellular processes, have been investigated as biomarkers of disease offering improved sensitivity and specificity in the diagnosis and prognostication of various conditions. In this review, the role of microRNAs as biomarkers used in the diagnosis of AMI and HF is discussed, their advantage over traditional biomarkers is outlined and the potential for their implementation in clinical practice is critically assessed.
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Affiliation(s)
- En C Fung
- Department of Laboratory Services, Raja Isteri Pengiran Anak Saleha (RIPAS) Hospital, Bandar Seri Begawan, Brunei Darussalam
| | - Asif N Butt
- Department of Clinical Biochemistry, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Jarlath Eastwood
- Aberdeen Royal Infirmary, NHS Grampian, Aberdeen, United Kingdom
| | - Ramasamyiyer Swaminathan
- Department of Clinical Biochemistry, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Ravinder Sodi
- Department of Blood Sciences, University Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster, United Kingdom; Lancaster Medical School, Lancaster University, Lancaster, United Kingdom.
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13
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Chen Y, Liu X, Chen L, Chen W, Zhang Y, Chen J, Wu X, Zhao Y, Wu X, Sun G. The long noncoding RNA XIST protects cardiomyocyte hypertrophy by targeting miR-330-3p. Biochem Biophys Res Commun 2018; 505:807-815. [PMID: 30297107 DOI: 10.1016/j.bbrc.2018.09.135] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Accepted: 09/20/2018] [Indexed: 12/16/2022]
Abstract
Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are implicated in numerous kinds of cardiovascular diseases, and their vital role in regulating cardiac hypertrophy still needs to be explored. In this study, we demonstrated that lncRNA X-inactive specific transcript (XIST) was upregulated in hypertrophic cardiac of mice and phenylephrine (PE)-treated cardiomyocytes. Next, we observed that inhibition of XIST induced hypertrophic response of cardiomyocyte and overexpression of XIST attenuated cardiomyocyte hypertrophy induced by PE. Furthermore, through online predictive tools and functional experiments, we demonstrated that XIST and S100B were targets of miR-330-3p. XIST and miR-330-3p suppressed each other in a reciprocal way in cardiomyocytes. Additionally, XIST promoted S100B expression through harboring the complementary binding sites with miR-330-3p, eventually prevented cardiac hypertrophy. In conclusion, our findings revealed a novel molecular mechanism that XIST/miR-330-3p/S100B pathway modulates the progression of cardiomyocyte hypertrophy.
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Affiliation(s)
- Yuewu Chen
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, China
| | - Xianxia Liu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, China.
| | - Lei Chen
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, China
| | - Weiwei Chen
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, China
| | - Yuansheng Zhang
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, China
| | - Jiaxian Chen
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, China
| | - Xuezheng Wu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, China
| | - Yong Zhao
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, China
| | - Xiaoyan Wu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, China
| | - Guowei Sun
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570100, Hainan Province, China
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14
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Oyama Y, Bartman CM, Gile J, Eckle T. Circadian MicroRNAs in Cardioprotection. Curr Pharm Des 2018; 23:3723-3730. [PMID: 28699517 DOI: 10.2174/1381612823666170707165319] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 06/27/2017] [Accepted: 07/04/2017] [Indexed: 12/23/2022]
Abstract
The most dramatic feature of life on Earth is our adaptation to the cycle of day and night. Throughout evolutionary time, almost all living organisms developed a molecular clock linked to the light-dark cycles of the sun. In present time, we know that this molecular clock is crucial to maintain metabolic and physiological homeostasis. Indeed, a dysregulated molecular clockwork is a major contributing factor to many metabolic diseases. In fact, the time of onset of acute myocardial infarction exhibits a circadian periodicity and recent studies have found that the light regulated circadian rhythm protein Period 2 (PER2) elicits endogenous cardioprotection from ischemia. Manipulating the molecular clockwork may prove beneficial during myocardial ischemia in humans. MicroRNAs are small non-coding RNA molecules capable of silencing messenger RNA (mRNA) targets. MicroRNA dysregulation has been linked to cancer development, cardiovascular and neurological diseases, lipid metabolism, and impaired immunity. Therefore, microRNAs are gaining interest as putative novel disease biomarkers and therapeutic targets. To identify circadian microRNA-based cardioprotective pathways, a recent study evaluated transcriptional changes of PER2 dependent microRNAs during myocardial ischemia. Out of 352 most abundantly expressed microRNAs, miR-21 was amongst the top PER2 dependent microRNAs and was shown to mediate PER2 elicited cardioprotection. Further analysis suggested circadian entrainment via intense light therapy to be a potential strategy to enhance miR-21 activity in humans. In this review, we will focus on circadian microRNAs in the context of cardioprotection and will highlight new discoveries, which could lead to novel therapeutic concepts to treat myocardial ischemia.
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Affiliation(s)
- Yoshimasa Oyama
- Department of Anesthesiology, University of Colorado Denver School of Medicine, Aurora, CO 80045. United States
| | - Colleen Marie Bartman
- Department of Anesthesiology, University of Colorado Denver School of Medicine, Aurora, CO 80045. United States
| | - Jennifer Gile
- Department of Anesthesiology, University of Colorado Denver School of Medicine, Aurora, CO 80045. United States
| | - Tobias Eckle
- Department of Anesthesiology, University of Colorado Denver, 12700 E 19th Avenue, Mailstop B112, RC 2, Room 7121, Aurora, CO 80045. United States
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15
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Identification of the miRNAome of early mesoderm progenitor cells and cardiomyocytes derived from human pluripotent stem cells. Sci Rep 2018; 8:8072. [PMID: 29795287 PMCID: PMC5966391 DOI: 10.1038/s41598-018-26156-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 05/01/2018] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs are small non-coding RNAs involved in post-transcriptional regulation of gene expression related to many cellular functions. We performed a small-RNAseq analysis of cardiac differentiation from pluripotent stem cells. Our analyses identified some new aspects about microRNA expression in this differentiation process. First, we described a dynamic expression profile of microRNAs where some of them are clustered according to their expression level. Second, we described the extensive network of isomiRs and ADAR modifications. Third, we identified the microRNAs families and clusters involved in the establishment of cardiac lineage and define the mirRNAome based on these groups. Finally, we were able to determine a more accurate miRNAome associated with cardiomyocytes by comparing the expressed microRNAs with other mature cells. MicroRNAs exert their effect in a complex and interconnected way, making necessary a global analysis to better understand their role. Our data expands the knowledge of microRNAs and their implications in cardiomyogenesis.
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16
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Shafei AES, Ali MA, Ghanem HG, Shehata AI, Abdelgawad AA, Handal HR, ElSayed AS, Ashaal AE, Ali MM, El-Shal AS. Mechanistic effects of mesenchymal and hematopoietic stem cells: New therapeutic targets in myocardial infarction. J Cell Biochem 2018; 119:5274-5286. [PMID: 29266431 DOI: 10.1002/jcb.26637] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 12/19/2017] [Indexed: 12/16/2022]
Abstract
Myocardial infarction (MI) results in dysfunction and irreversible loss of cardiomyocytes and is of the most serious health threats today. Mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) have been explored as promising cell therapy in MI and regenerative therapy. Recently, reports investigated the potential therapeutic effects of MSCs or HSCs transplantation after MI in numerous experimental and clinical studies; however, their results are controversy and needs more explorations. The current review is an attempt to clarify the therapeutic potentials of MSCs and HSCs in MI therapy, as well as their possible effects; especially the paracrine one and the exosome-derived stem cell among animal models as well as clinical trials conducted within the last 10 years. In this context, various sources of MSCs and HSCs have been addressed in helping cardiac regeneration by either revitalizing the cardiac stem cells niche or revascularizing the arteries and veins of the heart. In addition, both MSCs and HSCs could produce paracrine mediators and growth factors which led to cardiomyocytes protection, angiogenesis, immunemodulation, antioxidants, anti-apoptotic, anti-inflammatory, antifibrotic, as well as increasing cardiac contractility. Recently, microRNAs (miRNAs), post-transcriptional regulators of gene expression, and long non-coding RNA (lncRNA), a miRNA sponge, are recent stem cell-derived mediators can be promising targets of MSCs and HSCs through their paracrine effects. Although MSCs and HSCs have achieved considerable achievements, however, some challenges still remain that need to be overcome in order to establish it as a successful technique. The present review clarified the mechanistic potentials of MSCs and HSCs especially paracrine effects involved in MI including human and animal studies and the challenges challenges regarding type, differentiation, route, and number of injections.
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Affiliation(s)
- Ayman El-Sayed Shafei
- Biomedical Research Department, Military Armed Forces College of Medicine (AFCM), Cairo, Egypt
| | - Mahmoud A Ali
- Biomedical Research Department, Military Armed Forces College of Medicine (AFCM), Cairo, Egypt
| | - Hazem G Ghanem
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Ahmed I Shehata
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | | | - Hossam R Handal
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | | | - Ahmed E Ashaal
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Mazen M Ali
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Amal S El-Shal
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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17
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Tschöpe C, Van Linthout S, Kherad B. Heart Failure with Preserved Ejection Fraction and Future Pharmacological Strategies: a Glance in the Crystal Ball. Curr Cardiol Rep 2017; 19:70. [PMID: 28656481 DOI: 10.1007/s11886-017-0874-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW The current definition of heart failure is mainly based on an inappropriate measure of cardiac function, i.e., left ventricular ejection fraction (LVEF). The initial sole entity, heart failure with reduced ejection fraction (HFrEF, LVEF <40%), was complemented by the addition of heart failure with preserved ejection fraction (HFpEF, LVEF ≥50%) and most recently, heart failure with mid-range ejection fraction (HFmrEF, LVEF 40-49%). Initially, HFpEF was believed to be a purely left ventricular diastolic dysfunction. Pathophysiological concepts of HFpEF have changed considerably during the last years. In addition to intrinsic cardiac mechanisms, the heart failure pathogenesis is increasingly considered as driven by non-cardiac systemic processes including metabolic disorders, ischemic conditions, and pro-inflammatory/pro-fibrotic or immunological alterations. Presentation and pathophysiology of HFpEF is heterogeneous, and its management remains a challenge since evidence of therapeutic benefits is scarce. Up to now, there are no therapies improving survival in patients with HFpEF. RECENT FINDINGS Several results from clinical and preclinical interventions targeting non-cardiac mechanisms or non-pharmacological interventions including new anti-diabetic or anti-inflammatory drugs, mitochondrial-targeted anti-oxidants, anti-fibrotic strategies, microRNases incl. antagomirs, cell therapeutic options, and high-density lipoprotein-raising strategies are promising and under further investigation. This review addresses mechanisms and available data of current best clinical practice and novel approaches towards HFpEF.
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Affiliation(s)
- Carsten Tschöpe
- Department of Cardiology, Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany. .,Berliner Zentrum für Regenerative Therapien (BCRT), Campus Virchow Klinikum (CVK), Berlin, Germany. .,Deutsches Zentrum für Herz Kreislaufforschung (DZHK), Berlin, Germany. .,Campus Virchow Clinic, Department of Cardiology, Charité - Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353, Berlin, Germany.
| | - Sophie Van Linthout
- Berliner Zentrum für Regenerative Therapien (BCRT), Campus Virchow Klinikum (CVK), Berlin, Germany.,Deutsches Zentrum für Herz Kreislaufforschung (DZHK), Berlin, Germany.,Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Föhrerstrasse 15, 13353, Berlin, Germany
| | - Behrouz Kherad
- Department of Cardiology, Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany.,Campus Virchow Clinic, Department of Cardiology, Charité - Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353, Berlin, Germany.,Privatpraxis Dr. Kherad, Große Hamburger Strasse 5-11, 10115, Berlin, Germany
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18
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Shafei AES, Ali MA, Ghanem HG, Shehata AI, Abdelgawad AA, Handal HR, Talaat KA, Ashaal AE, El-Shal AS. Mesenchymal stem cell therapy: A promising cell-based therapy for treatment of myocardial infarction. J Gene Med 2017; 19. [PMID: 29044850 DOI: 10.1002/jgm.2995] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 10/07/2017] [Accepted: 10/07/2017] [Indexed: 12/12/2022] Open
Abstract
For decades, mesenchymal stem (MSCs) cells have been used for cardiovascular diseases as regenerative therapy. This review is an attempt to summarize the types of MSCs involved in myocardial infarction (MI) therapy, as well as its possible mechanisms effects, especially the paracrine one in MI focusing on the studies (human and animal) conducted within the last 10 years. Recently, reports showed that MSC therapy could have infarct-limiting effects after MI in both experimental and clinical trials. In this context, various types of MSCs can help cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Furthermore, MSCs could produce paracrine growth factors that increase the survival of nearby cardiomyocytes, as well as increase angiogenesis through recruitment of stem cell from bone marrow or inducing vessel growth from existing capillaries. Recent research suggests that the paracrine effects of MSCs could be mediated by extracellular vesicles including exosomes. Exosomal microRNAs (miRNAs) released by MSCs are promising therapeutic hotspot target for MI. This could be attributed to the role of miRNA in cardiac biology, including cardiac regeneration, stem cell differentiation, apoptosis, neovascularization, cardiac contractility and cardiac remodeling. Furthermore, gene-modified MSCs could be a recent promising therapy for MI to enhance the paracrine effects of MSCs, including better homing and effective cell targeted tissue regeneration. Although MSC therapy has achieved considerable attention and progress, there are critical challenges that remains to be overcome to achieve the most effective successful cell-based therapy in MI.
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Affiliation(s)
- Ayman El-Sayed Shafei
- Biomedical Research Department, Military Armed Forces College of Medicine, Cairo, Egypt
| | - Mahmoud Ahmed Ali
- Biomedical Research Department, Military Armed Forces College of Medicine, Cairo, Egypt
| | | | | | | | | | | | | | - Amal S El-Shal
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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19
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Frump AL, Bonnet S, de Jesus Perez VA, Lahm T. Emerging role of angiogenesis in adaptive and maladaptive right ventricular remodeling in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2017; 314:L443-L460. [PMID: 29097426 DOI: 10.1152/ajplung.00374.2017] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Right ventricular (RV) function is the primary prognostic factor for both morbidity and mortality in pulmonary hypertension (PH). RV hypertrophy is initially an adaptive physiological response to increased overload; however, with persistent and/or progressive afterload increase, this response frequently transitions to more pathological maladaptive remodeling. The mechanisms and disease processes underlying this transition are mostly unknown. Angiogenesis has recently emerged as a major modifier of RV adaptation in the setting of pressure overload. A novel paradigm has emerged that suggests that angiogenesis and angiogenic signaling are required for RV adaptation to afterload increases and that impaired and/or insufficient angiogenesis is a major driver of RV decompensation. Here, we summarize our current understanding of the concepts of maladaptive and adaptive RV remodeling, discuss the current literature on angiogenesis in the adapted and failing RV, and identify potential therapeutic approaches targeting angiogenesis in RV failure.
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Affiliation(s)
- Andrea L Frump
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana
| | - Sébastien Bonnet
- Pulmonary Hypertension Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University , Quebec City, Quebec , Canada
| | - Vinicio A de Jesus Perez
- Division of Pulmonary/Critical Care, Stanford University School of Medicine , Stanford, California.,Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine , Stanford, California
| | - Tim Lahm
- Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana.,Richard L. Roudebush Veterans Affairs Medical Center , Indianapolis, Indiana.,Department of Cellular and Integrative Physiology, Indiana University School of Medicine , Indianapolis, Indiana
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20
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Tschöpe C, Birner C, Böhm M, Bruder O, Frantz S, Luchner A, Maier L, Störk S, Kherad B, Laufs U. Heart failure with preserved ejection fraction: current management and future strategies : Expert opinion on the behalf of the Nucleus of the "Heart Failure Working Group" of the German Society of Cardiology (DKG). Clin Res Cardiol 2017; 107:1-19. [PMID: 29018938 DOI: 10.1007/s00392-017-1170-6] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 10/02/2017] [Indexed: 12/21/2022]
Abstract
About 50% of all patients suffering from heart failure (HF) exhibit a reduced ejection fraction (EF ≤ 40%), termed HFrEF. The others may be classified into HF with midrange EF (HFmrEF 40-50%) or preserved ejection fraction (HFpEF, EF ≥ 50%). Presentation and pathophysiology of HFpEF is heterogeneous and its management remains a challenge since evidence of therapeutic benefits on outcome is scarce. Up to now, there are no therapies improving survival in patients with HFpEF. Thus, the treatment targets symptom relief, quality of life and reduction of cardiac decompensations by controlling fluid retention and managing risk factors and comorbidities. As such, renin-angiotensin-aldosterone inhibitors, diuretics, calcium channel blockers (CBB) and beta-blockers, diet and exercise recommendations are still important in HFpEF, although these interventions are not proven to reduce mortality in large randomized controlled trials. Recently, numerous new treatment targets have been identified, which are further investigated in studies using, e.g. soluble guanylate cyclase stimulators, inorganic nitrates, the angiotensin receptor neprilysin inhibitor LCZ 696, and SGLT2 inhibitors. In addition, several devices such as the CardioMEMS, interatrial septal devices (IASD), cardiac contractility modulation (CCM), renal denervation, and baroreflex activation therapy (BAT) were investigated in different forms of HFpEF populations and some of them have the potency to offer new hopes for patients suffering from HFpEF. On the basic research field side, lot of new disease-modifying strategies are under development including anti-inflammatory drugs, mitochondrial-targeted antioxidants, new anti-fibrotic and microRNA-guided interventions are under investigation and showed already promising results. This review addresses available data of current best clinical practice and management approaches based on expert experiences and summarizes novel approaches towards HFpEF.
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Affiliation(s)
- Carsten Tschöpe
- Department of Cardiology, Universitätsmedizin Berlin, Charite, Campus Rudolf Virchow Clinic (CVK), Augustenburger Platz 1, 13353, Berlin, Germany. .,Berliner Zentrum für Regenerative Therapien (BCRT), Charite, Campus Virchow Clinic (CVK), Berlin, Germany. .,Deutsches Zentrum für Herz Kreislaufforschung (DZHK), Standort Berlin/Charité, Berlin, Germany.
| | - Christoph Birner
- Germany Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Michael Böhm
- Innere Medizin III-Kardiologie, Angiologie und internistische Intensivmedizin, Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Homburg, Germany
| | - Oliver Bruder
- Department of Cardiology and Angiology, Elisabeth Hospital, Essen, Germany
| | - Stefan Frantz
- Department of Internal Medicine III, University Halle, Halle, Germany
| | - Andreas Luchner
- Department of Internal Medicine I, Clinic St. Marien, Amberg, Germany
| | - Lars Maier
- Germany Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Stefan Störk
- Deutsches Zentrum für Herzinsuffizienz, Universitätsklinikum und Universität Würzburg, Würzburg, Germany
| | - Behrouz Kherad
- Department of Cardiology, Universitätsmedizin Berlin, Charite, Campus Rudolf Virchow Clinic (CVK), Augustenburger Platz 1, 13353, Berlin, Germany.,Privatpraxis Dr. Kherad, Berlin, Germany
| | - Ulrich Laufs
- Klinik und Poliklinik für Kardiologie im Department für Innere Medizin, Neurologie und Dermatologie, Universitätsklinikum Leipzig, Leipzig, Germany
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21
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Rotini A, Martínez-Sarrà E, Pozzo E, Sampaolesi M. Interactions between microRNAs and long non-coding RNAs in cardiac development and repair. Pharmacol Res 2017. [PMID: 28629929 DOI: 10.1016/j.phrs.2017.05.029] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Non-coding RNAs (ncRNAs) are emerging players in muscle regulation. Based on their length and differences in molecular structure, ncRNAs are subdivided into several categories including small interfering RNAs, stable non-coding RNAs, microRNAs (miRs), long non-coding RNAs (lncRNAs), and circular RNAs. miRs and lncRNAs are able to post-transcriptionally regulate many genes and bring into play several traits simultaneously due to a myriad of different targets. Recent studies have emphasized their importance in cardiac regeneration and repair. As their altered expression affects cardiac function, miRs and lncRNAs could be potential targets for therapeutic intervention. In this context, miR- and lncRNA-based gene therapies are an interesting field for harnessing the complexity of ncRNA-based therapeutic approaches in cardiac diseases. In this review we will focus on lncRNA- and miR-driven regulations of cardiac development and repair. Finally, we will summarize miRs and lncRNAs as promising candidates for the treatment of heart diseases.
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Affiliation(s)
- Alessio Rotini
- Translational Cardiomyology, Stem Cell Research Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, Herestraat 49 B-3000 Leuven, Belgium; Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy; Interuniversity Institute of Myology, Italy
| | - Ester Martínez-Sarrà
- Translational Cardiomyology, Stem Cell Research Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, Herestraat 49 B-3000 Leuven, Belgium; Regenerative Medicine Research Institute, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Enrico Pozzo
- Translational Cardiomyology, Stem Cell Research Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, Herestraat 49 B-3000 Leuven, Belgium
| | - Maurilio Sampaolesi
- Translational Cardiomyology, Stem Cell Research Institute, Stem Cell Biology and Embryology Unit, Department of Development and Regeneration, KU Leuven, Herestraat 49 B-3000 Leuven, Belgium; Human Anatomy Unit, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Via Forlanini 8, 27100 Pavia, Italy.
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22
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Sun Y, Su Q, Li L, Wang X, Lu Y, Liang J. MiR-486 regulates cardiomyocyte apoptosis by p53-mediated BCL-2 associated mitochondrial apoptotic pathway. BMC Cardiovasc Disord 2017; 17:119. [PMID: 28486954 PMCID: PMC5424355 DOI: 10.1186/s12872-017-0549-7] [Citation(s) in RCA: 40] [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: 12/19/2016] [Accepted: 05/02/2017] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Cardiomyocyte apoptosis is a common pathological manifestation that occurs in several heart diseases. This study aimed to explore the mechanism of microRNA-486 (miR-486) in cardiomyocyte apoptosis by interfering with the p53-activated BCL-2 associated mitochondrial pathway. METHODS miR-486 mimics and inhibitors were transfected into the primary cardiomyocytes of suckling Sprague-Dawley rat pups, and H2O2 was used to induce apoptosis. Flow cytometry and TUNEL were both used to detect cardiomyocyte apoptosis, while the relative mRNA transcript and protein levels of miR-486, p53, Bbc3, BCL-2, and cleaved caspase-3 were detected using RT-PCR and western blot analysis, respectively. RESULTS miR-486 overexpression significantly decreased the expressions of p53, Bbc3 and cleaved caspase-3 (P < 0.05), and BCL-2 expression was significantly increased (P < 0.05), which in turn caused a significant decrease in the rate of cardiomyocyte apoptosis (P < 0.05). In contrast, miR-486 silencing resulted in an elevated rate of cardiomyocyte apoptosis (P < 0.05). CONCLUSION miR-486 may regulate cardiomyocyte apoptosis via p53-mediated BCL-2 associated mitochondrial apoptotic pathway. Therefore, up-regulating miR-486 expression in cardiomyocytes can effectively reduce the activation of the BCL-2 associated mitochondrial apoptotic pathway, consequently protecting cardiomyocytes.
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MESH Headings
- Animals
- Animals, Suckling
- Apoptosis/drug effects
- Cells, Cultured
- Gene Expression Regulation
- Hydrogen Peroxide/toxicity
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Mitochondria, Heart/drug effects
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/pathology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Proto-Oncogene Proteins c-bcl-2/genetics
- Proto-Oncogene Proteins c-bcl-2/metabolism
- RNA Interference
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Rats, Sprague-Dawley
- Signal Transduction
- Transfection
- Tumor Suppressor Protein p53/genetics
- Tumor Suppressor Protein p53/metabolism
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Affiliation(s)
- Yuhan Sun
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 China
| | - Qiang Su
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 China
| | - Lang Li
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 China
| | - Xiantao Wang
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 China
| | - Yuanxi Lu
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 China
| | - Jiabao Liang
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 China
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23
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van Middendorp LB, Kuiper M, Munts C, Wouters P, Maessen JG, van Nieuwenhoven FA, Prinzen FW. Local microRNA-133a downregulation is associated with hypertrophy in the dyssynchronous heart. ESC Heart Fail 2017; 4:241-251. [PMID: 28772031 PMCID: PMC5542733 DOI: 10.1002/ehf2.12154] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 01/18/2017] [Accepted: 02/22/2017] [Indexed: 11/18/2022] Open
Abstract
Aims Left bundle branch block (LBBB) creates considerable regional differences in mechanical load within the left ventricle (LV). We investigated expression of selected microRNAs (miRs) in relation to regional hypertrophy and fibrosis in LBBB hearts and their reversibility upon cardiac resynchronization therapy (CRT). Methods and results Eighteen dogs were followed for 4 months after induction of LBBB, 10 of which received CRT after 2 months. Five additional dogs served as control. LV geometric changes were determined by echocardiography and myocardial strain by magnetic resonance imaging tagging. Expression levels of miRs, their target genes: connective tissue growth factor (CTGF), serum response factor (SRF), nuclear factor of activated T cells (NFATc4), and cardiomyocyte diameter and collagen deposition were measured in the septum and LV free wall (LVfw). In LBBB hearts, LVfw and septal systolic circumferential strain were 200% and 50% of control, respectively. This coincided with local hypertrophy in the LVfw. MiR‐133a expression was reduced by 33% in the LVfw, which corresponded with a selective increase of CTGF expression in the LVfw (279% of control). By contrast, no change was observed in SRF and NFATc4 expression was decreased in LBBB hearts. CRT normalized strain patterns and reversed miR‐133a and CTGF expression towards normal, expression of other miRs, related to remodelling, such as miR‐199b and miR‐155f, were not affected. Conclusions In the clinically relevant large animal model of LBBB, a close inverse relation exists between local hypertrophy and miR‐133a. Reduced miR‐133a correlated with increased CTGF levels but not with SRF and NFATc4.
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Affiliation(s)
- Lars B van Middendorp
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Limburg, The Netherlands.,Department of Cardiothoracic Surgery, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Limburg, The Netherlands
| | - Marion Kuiper
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Limburg, The Netherlands
| | - Chantal Munts
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Limburg, The Netherlands
| | - Philippe Wouters
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Limburg, The Netherlands
| | - Jos G Maessen
- Department of Cardiothoracic Surgery, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Limburg, The Netherlands
| | - Frans A van Nieuwenhoven
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Limburg, The Netherlands
| | - Frits W Prinzen
- Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Limburg, The Netherlands
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Liu J, Liu T, Wang X, He A. Circles reshaping the RNA world: from waste to treasure. Mol Cancer 2017; 16:58. [PMID: 28279183 PMCID: PMC5345220 DOI: 10.1186/s12943-017-0630-y] [Citation(s) in RCA: 327] [Impact Index Per Article: 40.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 03/02/2017] [Indexed: 02/08/2023] Open
Abstract
A new type of RNAs was identified from genes traditionally thought to express messenger or linear ncRNA (noncoding RNA) only. They were subsequently named as circRNAs (circular RNAs) due to the covalently closed structure. Accumulating studies were performed to explore the expression profile of circRNAs in different cell types and diseases, the outcomes totally changed our view of ncRNAs, which was thought to be junk by-products in the process of gene transcription, and enriched our poor understanding of its underlying functions. The expression profile of circRNAs is tissue-specific and alters across various stages of cell differentiation. The biological function of circRNAs is multi-faceted, involving five main features (sponge effect, post-transcriptional regulation, rolling circle translation, circRNA-derived pseudogenes and splicing interference) and varying differently from the locations, binding sites and acting modes of circRNAs. The regulating role of circRNAs is not isolated but through an enormous complicated network involving mRNAs, miRNAs and proteins. Although most of the potential functions still remain unclear, circRNAs have been proved to be ubiquitous and critical in regulating cellular processes and diseases, especially in cancers, from the laboratory to the clinic. Herein, we review circRNAs’ classification, biogenesis and metabolism, their well-studied and anticipated functions, the current understanding of the potential implications of circRNAs in tumorigenesis and cancer targeted therapy.
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Affiliation(s)
- Jing Liu
- Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University Health Care Center, 157 West 5 Street, Xi'an, 710004, Shaanxi, People's Republic of China
| | - Tian Liu
- Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University Health Care Center, 157 West 5 Street, Xi'an, 710004, Shaanxi, People's Republic of China
| | - Xiaman Wang
- Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University Health Care Center, 157 West 5 Street, Xi'an, 710004, Shaanxi, People's Republic of China
| | - Aili He
- Department of Clinical Hematology, Second Affiliated Hospital, Xi'an Jiaotong University Health Care Center, 157 West 5 Street, Xi'an, 710004, Shaanxi, People's Republic of China.
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25
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Herring BP, Hoggatt AM, Griffith SL, McClintick JN, Gallagher PJ. Inflammation and vascular smooth muscle cell dedifferentiation following carotid artery ligation. Physiol Genomics 2016; 49:115-126. [PMID: 28039430 PMCID: PMC5374455 DOI: 10.1152/physiolgenomics.00095.2016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 12/21/2016] [Accepted: 12/21/2016] [Indexed: 11/22/2022] Open
Abstract
Following vascular injury medial smooth muscle cells dedifferentiate and migrate through the internal elastic lamina where they form a neointima. The goal of the current study was to identify changes in gene expression that occur before the development of neointima and are associated with the early response to injury. Vascular injury was induced in C57BL/6 mice and in Myh11-creER(T2) mTmG reporter mice by complete ligation of the left carotid artery. Reporter mice were used to visualize cellular changes in the injured vessels. Total RNA was isolated from control carotid arteries or from carotid arteries 3 days following ligation of C57BL/6 mice and analyzed by Affymetrix microarray and quantitative RT-PCR. This analysis revealed decreased expression of mRNAs encoding smooth muscle-specific contractile proteins that was accompanied by a marked increase in a host of mRNAs encoding inflammatory cytokines following injury. There was also marked decrease in molecules associated with BMP, Wnt, and Hedgehog signaling and an increase in those associated with B cell, T cell, and macrophage signaling. Expression of a number of noncoding RNAs were also altered following injury with microRNAs 143/145 being dramatically downregulated and microRNAs 1949 and 142 upregulated. Several long noncoding RNAs showed altered expression that mirrored the expression of their nearest coding genes. These data demonstrate that following carotid artery ligation an inflammatory cascade is initiated that is associated with the downregulation of coding and noncoding RNAs that are normally required to maintain smooth muscle cells in a differentiated state.
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Affiliation(s)
- B Paul Herring
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; and
| | - April M Hoggatt
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; and
| | - Sarah L Griffith
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; and
| | - Jeanette N McClintick
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Patricia J Gallagher
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; and
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26
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Bian EB, Wang YY, Yang Y, Wu BM, Xu T, Meng XM, Huang C, Zhang L, Lv XW, Xiong ZG, Li J. Hotair facilitates hepatic stellate cells activation and fibrogenesis in the liver. Biochim Biophys Acta Mol Basis Dis 2016; 1863:674-686. [PMID: 27979710 DOI: 10.1016/j.bbadis.2016.12.009] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 11/25/2016] [Accepted: 12/12/2016] [Indexed: 12/18/2022]
Abstract
Long non-coding RNAs (lncRNAs) are increasingly recognized as major players in regulating various biological processes. LncRNA HOX transcript antisense RNA (Hotair) has been extensively studied in cancer. However, the role of Hotair in liver fibrosis remains unknown. Here we observed that Hotair expression was significantly increased in CCl4-induced mouse liver fibrosis models, human fibrotic livers and activated hepatic stellate cells (HSCs) by TGF-β1 stimulation. Enforced expression of Hotair in LX-2 cells promoted cell proliferation and activation while inhibition of its expression had an opposite effect. Furthermore, we found that Hotair may act as an endogenous 'sponge' of miR-148b, which regulates expression of the DNMT1/MEG3/p53 pathways in HSCs. Intriguingly, Hotair enhanced polycomb repressive complex 2 (PRC2) occupancy and histone H3K27me3 repressive marks, specifically at the MEG3 promoter region. Finally, we found that Hotair forms an RNA/DNA hybrid and recruits PRC2 to MEG3 promoter. These data suggest that Hotair inhibition may represent a promising therapeutic option for suppressing liver fibrosis.
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Affiliation(s)
- Er-Bao Bian
- School of pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), Hefei 230032, China
| | - Yuan-Yuan Wang
- School of pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), Hefei 230032, China
| | - Yang Yang
- School of pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), Hefei 230032, China
| | - Bao-Ming Wu
- School of pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), Hefei 230032, China
| | - Tao Xu
- School of pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), Hefei 230032, China
| | - Xiao-Ming Meng
- School of pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), Hefei 230032, China
| | - Cheng Huang
- School of pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), Hefei 230032, China
| | - Lei Zhang
- School of pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), Hefei 230032, China
| | - Xiong-Wen Lv
- School of pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), Hefei 230032, China
| | - Zhi-Gang Xiong
- School of pharmacy, Anhui Medical University, Hefei 230032, China; Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW, Atlanta, GA 30310-1945, USA.
| | - Jun Li
- School of pharmacy, Anhui Medical University, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University (AMU), Hefei 230032, China.
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27
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The long noncoding RNA NRF regulates programmed necrosis and myocardial injury during ischemia and reperfusion by targeting miR-873. Cell Death Differ 2016; 23:1394-405. [PMID: 27258785 DOI: 10.1038/cdd.2016.28] [Citation(s) in RCA: 174] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 11/29/2016] [Accepted: 01/08/2016] [Indexed: 02/08/2023] Open
Abstract
Emerging evidences suggest that necrosis is programmed and is one of the main forms of cell death in the pathological process in cardiac diseases. Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation. However, it is not yet clear whether lncRNAs can regulate necrosis in cardiomyocytes. Here, we report that a long noncoding RNA, named necrosis-related factor (NRF), regulates cardiomyocytes necrosis by targeting miR-873 and RIPK1 (receptor-interacting serine/threonine-protein kinase 1)/RIPK3 (receptor-interacting serine/threonine-protein kinase 3). Our results show that RIPK1 and RIPK3 participate in H2O2-induced cardiomyocytes necrosis. miR-873 suppresses the translation of RIPK1/RIPK3 and inhibits RIPK1/RIPK3-mediated necrotic cell death in cardiomyocytes. miR-873 reduces myocardial infarct size upon ischemia/reperfusion (I/R) injury in the animal model. In exploring the molecular mechanism by which miR-873 expression is regulated, we identify NRF as an endogenous sponge RNA and repress miR-873 expression. NRF directly binds to miR-873 and regulates RIPK1/RIPK3 expression and necrosis. Knockdown of NRF antagonizes necrosis in cardiomyocytes and reduces necrosis and myocardial infarction upon I/R injury. Further, we identify that p53 transcriptionally activates NRF expression. P53 regulates cardiomyocytes necrosis and myocardial I/R injury through NRF and miR-873.Our results identify a novel mechanism involving NRF and miR-873 in regulating programmed necrosis in the heart and suggest a potential therapeutic avenue for cardiovascular diseases.
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28
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Wang K, Long B, Liu F, Wang JX, Liu CY, Zhao B, Zhou LY, Sun T, Wang M, Yu T, Gong Y, Liu J, Dong YH, Li N, Li PF. A circular RNA protects the heart from pathological hypertrophy and heart failure by targeting miR-223. Eur Heart J 2016; 37:2602-11. [PMID: 26802132 DOI: 10.1093/eurheartj/ehv713] [Citation(s) in RCA: 710] [Impact Index Per Article: 78.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 12/04/2015] [Indexed: 12/14/2022] Open
Abstract
AIMS Sustained cardiac hypertrophy accompanied by maladaptive cardiac remodelling represents an early event in the clinical course leading to heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. However, the molecular mechanisms that regulate cardiac hypertrophy are largely unknown. METHODS AND RESULTS Here we show that a circular RNA (circRNA), which we term heart-related circRNA (HRCR), acts as an endogenous miR-223 sponge to inhibit cardiac hypertrophy and heart failure. miR-223 transgenic mice developed cardiac hypertrophy and heart failure, whereas miR-223-deficient mice were protected from hypertrophic stimuli, indicating that miR-223 acts as a positive regulator of cardiac hypertrophy. We identified ARC as a miR-223 downstream target to mediate the function of miR-223 in cardiac hypertrophy. Apoptosis repressor with CARD domain transgenic mice showed reduced hypertrophic responses. Further, we found that a circRNA HRCR functions as an endogenous miR-223 sponge to sequester and inhibit miR-223 activity, which resulted in the increase of ARC expression. Heart-related circRNA directly bound to miR-223 in cytoplasm and enforced expression of HRCR in cardiomyocytes and in mice both exhibited attenuated hypertrophic responses. CONCLUSIONS These findings disclose a novel regulatory pathway that is composed of HRCR, miR-223, and ARC. Modulation of their levels provides an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure.
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Affiliation(s)
- Kun Wang
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Bo Long
- Laboratory of Molecular Medicine, Central Research Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing100730, China
| | - Fang Liu
- Department of Anatomy, College of Basic Medicine, Guilin Medical University, Guilin 541004, China
| | - Jian-Xun Wang
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Cui-Yun Liu
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Bing Zhao
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Lu-Yu Zhou
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Teng Sun
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Man Wang
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Tao Yu
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Ying Gong
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jia Liu
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yan-Han Dong
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Na Li
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Pei-Feng Li
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
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29
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Pisano F, Altomare C, Cervio E, Barile L, Rocchetti M, Ciuffreda MC, Malpasso G, Copes F, Mura M, Danieli P, Viarengo G, Zaza A, Gnecchi M. Combination of miRNA499 and miRNA133 exerts a synergic effect on cardiac differentiation. Stem Cells 2016; 33:1187-99. [PMID: 25534971 PMCID: PMC4409033 DOI: 10.1002/stem.1928] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Revised: 11/13/2014] [Accepted: 11/21/2014] [Indexed: 12/16/2022]
Abstract
Several studies have demonstrated that miRNA are involved in cardiac development, stem cell maintenance, and differentiation. In particular, it has been shown that miRNA133, miRNA1, and miRNA499 are involved in progenitor cell differentiation into cardiomyocytes. However, it is unknown whether different miRNA may act synergistically to improve cardiac differentiation. We used mouse P19 cells as a cardiogenic differentiation model. miRNA499, miRNA1, or miRNA133 were transiently over-expressed in P19 cells individually or in different combinations. The over-expression of miRNA499 alone increased the number of beating cells and the association of miRNA499 with miRNA133 exerted a synergistic effect, further increasing the number of beating cells. Real-time polymerase chain reaction showed that the combination of miRNA499 + 133 enhanced the expression of cardiac genes compared with controls. Western blot and immunocytochemistry for connexin43 and cardiac troponin T confirmed these findings. Importantly, caffeine responsiveness, a clear functional parameter of cardiac differentiation, was increased by miRNA499 in association with miRNA133 and was directly correlated with the activation of the cardiac troponin I isoform promoter. Cyclic contractions were reversibly abolished by extracellular calcium depletion, nifedipine, ryanodine, and IP3R blockade. Finally, we demonstrated that the use of miRNA499 + 133 induced cardiac differentiation even in the absence of dimethyl sulfoxide. Our results show that the areas spontaneously contracting possess electrophysiological and pharmacological characteristics compatible with true cardiac excitation-contraction coupling. The translational relevance of our findings was reinforced by the demonstration that the over-expression of miRNA499 and miRNA133 was also able to induce the differentiation of human mesenchymal stromal cells toward the cardiac lineage. Stem Cells2015;33:1187–1199
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Affiliation(s)
- Federica Pisano
- Department of Cardiothoracic and Vascular Sciences-Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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30
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Wang K, Zhou LY, Wang JX, Wang Y, Sun T, Zhao B, Yang YJ, An T, Long B, Li N, Liu CY, Gong Y, Gao JN, Dong YH, Zhang J, Li PF. E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1. Nat Commun 2015; 6:7619. [PMID: 26184432 DOI: 10.1038/ncomms8619] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 05/25/2015] [Indexed: 12/23/2022] Open
Abstract
Mitochondrial fragmentation plays an important role in the progression of cardiac diseases, such as myocardial infarction and heart failure. Mitochondrial network is controlled by many factors in different cell types. Here we show that the interplay between E2F1, miR-421 and Pink1 regulates mitochondrial morphology and cardiomyocyte cell death. Pink1 reduces mitochondrial fragmentation and protects cardiomyocyte from apoptosis. On the other hand, miR-421 promotes cardiomyocyte mitochondrial fragmentation, apoptosis and myocardial infarction by suppressing Pink1 translation. Finally, we show that transcription factor E2F1 activates miR-421 expression. Knocking down E2F1 suppresses mitochondrial fragmentation, apoptosis and myocardial infarction by affecting miR-421 levels. Collectively, these data identify the E2F1/miR-421/Pink axis as a regulator of mitochondrial fragmentation and cardiomyocyte apoptosis, and suggest potential therapeutic targets in treatment of cardiac diseases.
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Affiliation(s)
- Kun Wang
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Lu-Yu Zhou
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jian-Xun Wang
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yin Wang
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Teng Sun
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Bing Zhao
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yong-Jie Yang
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Tao An
- State Key Laboratory of Cardiovascular Disease, Heart Failure center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Bo Long
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Na Li
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Cui-Yun Liu
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Ying Gong
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jin-Ning Gao
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yan-Han Dong
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Jian Zhang
- State Key Laboratory of Cardiovascular Disease, Heart Failure center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100037, China
| | - Pei-Feng Li
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
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[Epigenetics in atherosclerosis]. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2015; 28:102-19. [PMID: 26088002 DOI: 10.1016/j.arteri.2015.04.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Revised: 04/14/2015] [Accepted: 04/15/2015] [Indexed: 12/13/2022]
Abstract
The association studies based on candidate genes carried on for decades have helped in visualizing the influence of the genetic component in complex diseases such as atherosclerosis, also showing the interaction between different genes and environmental factors. Even with all the knowledge accumulated, there is still some way to go to decipher the individual predisposition to disease, and if we consider the great influence that environmental factors play in the development and progression of atherosclerosis, epigenetics is presented as a key element in trying to expand our knowledge on individual predisposition to atherosclerosis and cardiovascular disease. Epigenetics can be described as the discipline that studies the mechanisms of transcriptional regulation, independent of changes in the sequence of DNA, and mostly induced by environmental factors. This review aims to describe what epigenetics is and how epigenetic mechanisms are involved in atherosclerosis.
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Wang K, An T, Zhou LY, Liu CY, Zhang XJ, Feng C, Li PF. E2F1-regulated miR-30b suppresses Cyclophilin D and protects heart from ischemia/reperfusion injury and necrotic cell death. Cell Death Differ 2015; 22:743-54. [PMID: 25301066 PMCID: PMC4392072 DOI: 10.1038/cdd.2014.165] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 08/10/2014] [Accepted: 09/01/2014] [Indexed: 12/16/2022] Open
Abstract
Cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Cell death is a hallmark characteristic of various cardiac diseases, including myocardial infarction and heart failure. Emerging evidences suggest that necrosis is programmed and is one of the main forms of cell death in the pathological process in cardiac diseases. However, the molecular components regulating programmed necrosis in heart remain largely unidentified. Here we report that miR-30b, Cyclophilin D (CypD) and E2F1 constitute an axis that regulates necrosis. The results show that knockdown of CypD attenuated necrosis in the cellular model and also myocardial infarction in the animal model. miR-30b suppresses the translation of CypD and thus inhibits CypD-mediated necrotic cell death in cardiomyocytes. Cardiac-specific miR-30b transgenic mice exhibit reduced necrosis and myocardial infarct size upon ischemia/reperfusion (I/R) injury. Further, we identify that E2F1 transcriptionally represses miR-30b expression. Knockdown of E2F1 in cardiomyocytes inhibits necrotic cell death, and E2F1 knockout mice show reduced necrosis and myocardial infarct size upon I/R. Our present study identifies a novel signaling pathway composed of E2F1, miR-30b and CypD that regulates myocardial necrosis. This discovery will not only provide de novo regulators in the necrotic process but will also shed new light on the effective therapy of myocardial infarction and heart failure.
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Affiliation(s)
- K Wang
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - T An
- State Key Laboratory of Cardiovascular Disease, Heart Failure center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - L-Y Zhou
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
| | - C-Y Liu
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - X-J Zhang
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - C Feng
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - P-F Li
- Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
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Abstract
Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Although the translation of ischemic postconditioning and remote ischemic conditioning protocols to patients with acute myocardial infarction has been fairly successful, the pharmacological recruitment of cardioprotective signaling has been largely disappointing to date.
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Affiliation(s)
- Gerd Heusch
- From the Institute for Pathophysiology, West German Heart and Vascular Centre, University of Essen Medical School, Essen, Germany.
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[New therapy concepts for heart failure with preserved ejection fraction]. Herz 2015; 40:194-205. [PMID: 25737289 DOI: 10.1007/s00059-015-4210-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The management of patients with heart failure and preserved ejection fraction (HFpEF) remains challenging and requires an accurate diagnosis. Although currently no convincing therapy that can prolong survival in patients with HFpEF has been established, treatment of fluid retention, heart rate and control of comorbidities are important cornerstones to improve the quality of life and symptoms. In recent years many new therapy targets have been tested for development of successful interventional strategies for HFpEF. Insights into new mechanisms of HFpEF have shown that heart failure is associated with dysregulation of the nitric oxide-cyclic guanosine monophosphate-protein kinase (NO-cGMP-PK) pathway. Two new drugs are currently under investigation to test whether this pathway can be significantly improved by either the neprilysin inhibitor LCZ 696 due to an increase in natriuretic peptides or by the soluble guanylate cyclase stimulator vericiguat, which is also able to increase cGMP. In addition, several preclinical or early phase studies which are currently investigating new mechanisms for matrix, intracellular calcium and energy regulation including the role of microRNAs and new devices are presented and discussed.
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miR-361-regulated prohibitin inhibits mitochondrial fission and apoptosis and protects heart from ischemia injury. Cell Death Differ 2014; 22:1058-68. [PMID: 25501599 DOI: 10.1038/cdd.2014.200] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 10/07/2014] [Accepted: 10/20/2014] [Indexed: 11/08/2022] Open
Abstract
Cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Emerging evidences suggest that the abnormal mitochondrial fission participates in pathogenesis of cardiac diseases, including myocardial infarction (MI) and heart failure. However, the molecular components regulating mitochondrial network in the heart remain largely unidentified. Here we report that miR-361 and prohibitin 1 (PHB1) constitute an axis that regulates mitochondrial fission and apoptosis. The results show that PHB1 attenuates mitochondrial fission and apoptosis in response to hydrogen peroxide treatment in cardiomyocytes. Cardiac-specific PHB1 transgenic mice show reduced mitochondrial fission and myocardial infarction sizes after myocardial infarction surgery. MiR-361 is responsible for the dysfunction of PHB1 and suppresses the translation of PHB1. Knockdown of miR-361 reduces mitochondrial fission and apoptosis in vivo and in vitro. MiR-361 cardiac-specific transgenic mice represent elevated mitochondrial fission and myocardial infarction sizes upon myocardial ischemia injury. This study identifies a novel signaling pathway composed of miR-361 and PHB1 that regulates mitochondrial fission program and apoptosis. This discovery will shed new light on the therapy of myocardial infarction and heart failure.
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Izarra A, Moscoso I, Cañón S, Carreiro C, Fondevila D, Martín-Caballero J, Blanca V, Valiente I, Díez-Juan A, Bernad A. miRNA-1 and miRNA-133a are involved in early commitment of pluripotent stem cells and demonstrate antagonistic roles in the regulation of cardiac differentiation. J Tissue Eng Regen Med 2014; 11:787-799. [PMID: 25492026 DOI: 10.1002/term.1977] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Revised: 09/09/2014] [Accepted: 11/07/2014] [Indexed: 12/18/2022]
Abstract
miRNA-1 (miR-1) and miRNA-133a (miR-133a) are muscle-specific miRNAs that play an important role in heart development and physiopathology. Although both miRNAs have been broadly studied during cardiogenesis, the mechanisms by which miR-1 and miR-133a could influence linage commitment in pluripotent stem cells remain poorly characterized. In this study we analysed the regulation of miR-1 and miR-133a expression during pluripotent stem cell differentiation [P19.CL6 cells; embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)] and investigated their role in DMSO and embryoid body (EB)-mediated mesodermal and cardiac differentiation by gain- and loss-of-function studies, as well as in vivo, by the induction of teratomas. Gene expression analysis revealed that miR-1 and miR-133a are upregulated during cardiac differentiation of P19.CL6 cells, and also during ESC and iPSC EB differentiation. Forced overexpression of both miRNAs promoted mesodermal commitment and a concomitant decrease in the expression of neural differentiation markers. Moreover, overexpression of miR-1 enhanced the cardiac differentiation of P19.CL6, while miR-133a reduced it with respect to control cells. Teratoma formation experiments with P19.CL6 cells confirmed the influence of miR-1 and miR-133a during in vivo differentiation. Finally, inhibition of both miRNAs during P19.CL6 cardiac differentiation had opposite results to their overexpression. In conclusion, gene regulation involving miR-1 and miR-133a controls the mesodermal and cardiac fate of pluripotent stem cells. Copyright © 2014 John Wiley & Sons, Ltd.
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Affiliation(s)
- Alberto Izarra
- Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.,Immunology and Oncology Department, National Centre for Biotechnology, CSIC, Madrid, Spain
| | - Isabel Moscoso
- Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.,Cardiovascular Area, CIMUS, Instituto de Investigación Sanitaria, University of Santiago de Compostela, Spain
| | - Susana Cañón
- Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.,Immunology and Oncology Department, National Centre for Biotechnology, CSIC, Madrid, Spain
| | - Candelas Carreiro
- Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Dolors Fondevila
- Departament de Medicina i Cirurgia Animals, Universitat Autònoma de Barcelona, Spain
| | | | - Vanessa Blanca
- Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Iñigo Valiente
- Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Antonio Díez-Juan
- Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.,Instituto de Investigación Sanitaria INCLIVA, Valencia, Spain
| | - Antonio Bernad
- Department of Cardiovascular Development and Repair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.,Immunology and Oncology Department, National Centre for Biotechnology, CSIC, Madrid, Spain
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Chen J, Zhao X, Wang H, Chen Y, Wang W, Zhou W, Wang X, Tang J, Zhao Y, Lu X, Chen S, Wang L, Shen C, Yang S. Common variants in TGFBR2 and miR-518 genes are associated with hypertension in the Chinese population. Am J Hypertens 2014; 27:1268-76. [PMID: 24687999 DOI: 10.1093/ajh/hpu047] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND An animal study reported that TGF-β1 maturation was linked to the homeostasis of blood pressure and elastogenesis of essential hypertension (EH). Recent advances require further research of TGF-β1 receptor in EH. METHODS A case-control study comprised of 2,012 adult hypertension case patients and 2,210 adult control subjects was conducted, and the association with blood pressure was further tested in children. Logistic regression and calculated genetic risk score were used to evaluate the effects of one single nucleotide polymorphism (SNP) and multiple SNPs on EH, respectively. RESULTS The genetic risk score of 10 SNPs showed a significant association with hypertension; the odds ratio of the upper quartile vs. the lower quartile was 1.282 (P = 4.67 × 10(-3)). rs7256241 in miR-518 was significantly associated with diastolic blood pressure (DBP) change in control subjects (P = 0.002), and this association was also observed in children (P = 0.04). The systolic blood pressure (SBP) and DBP of female patients taking reserpine were higher with the C and G alleles of rs3773661 (P = 0.004) and rs7256241 (P = 0.002), respectively. In patients taking Zhen Ju Jiang Ya tablets, SBP and DBP decreased linearly with rs749794 (P = 0.004 and P = 0.048, respectively). SBP decreased linearly with rs1155705 (P = 0.007) and rs11709624 (P = 0.04), but increased with rs1036096 (P = 0.03) in male patients. In male patients taking Jiang Ya tablets, SBP increased linearly with rs11709624 (P = 0.007), DBP increased linearly with rs1155705 (P = 0.03) whereas decreased with rs7256241 (P = 0.04). CONCLUSIONS Our results suggest that TGFBR2 and miR-518 harbor variants that increase the risk of EH and affect blood pressure homeostasis as well as efficacy of antihypertensive agents.
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Affiliation(s)
- Jinfeng Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Province Institute of Geriatrics, Nanjing, China
| | - Xianghai Zhao
- Department of Cardiology, Affiliated Yixing People's Hospital of Jiangsu University, People's Hospital of Yixing City, Yixing, China
| | - Hairu Wang
- Nanjing Institute of Industry Technology, Nanjing, China
| | - Yanchun Chen
- Department of Cardiology, Affiliated Yixing People's Hospital of Jiangsu University, People's Hospital of Yixing City, Yixing, China
| | - Wen Wang
- Department of Cardiology, Affiliated Yixing People's Hospital of Jiangsu University, People's Hospital of Yixing City, Yixing, China
| | - Wei Zhou
- Department of Cardiology, Affiliated Yixing People's Hospital of Jiangsu University, People's Hospital of Yixing City, Yixing, China
| | - Xuecai Wang
- Department of Clinical Laboratory, Affiliated Yixing People's Hospital of Jiangsu University, People's Hospital of Yixing City, Yixing, China
| | - Junming Tang
- Department of Clinical Laboratory, Affiliated Yixing People's Hospital of Jiangsu University, People's Hospital of Yixing City, Yixing, China
| | - Yanping Zhao
- Department of Neurology, Affiliated Yixing People's Hospital of Jiangsu University, People's Hospital of Yixing City, Yixing, China
| | - Xiangfeng Lu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shufeng Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Laiyuan Wang
- National Human Genome Center at Beijing, Beijing, China
| | - Chong Shen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China;
| | - Song Yang
- Department of Cardiology, Affiliated Yixing People's Hospital of Jiangsu University, People's Hospital of Yixing City, Yixing, China
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Tan X, Gong YZ, Wu P, Liao DF, Zheng XL. Mesenchymal stem cell-derived microparticles: a promising therapeutic strategy. Int J Mol Sci 2014; 15:14348-63. [PMID: 25196436 PMCID: PMC4159854 DOI: 10.3390/ijms150814348] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Revised: 07/25/2014] [Accepted: 08/04/2014] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells that give rise to various cell types of the mesodermal germ layer. Because of their unique ability to home in on injured and cancerous tissues, MSCs are of great potential in regenerative medicine. MSCs also contribute to reparative processes in different pathological conditions, including cardiovascular diseases and cancer. However, many studies have shown that only a small proportion of transplanted MSCs can actually survive and be incorporated into host tissues. The effects of MSCs cannot be fully explained by their number. Recent discoveries suggest that microparticles (MPs) derived from MSCs may be important for the physiological functions of their parent. Though the physiological role of MSC-MPs is currently not well understood, inspiring results indicate that, in tissue repair and anti-cancer therapy, MSC-MPs have similar pro-regenerative and protective properties as their cellular counterparts. Thus, MSC-MPs represent a promising approach that may overcome the obstacles and risks associated with the use of native or engineered MSCs.
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Affiliation(s)
- Xi Tan
- Division of Stem Cell Regulation and Application, College of Medicine, Hunan University of Traditional Chinese Medicine, Changsha 410208, China.
| | - Yong-Zhen Gong
- Division of Stem Cell Regulation and Application, College of Medicine, Hunan University of Traditional Chinese Medicine, Changsha 410208, China.
| | - Ping Wu
- Division of Stem Cell Regulation and Application, College of Medicine, Hunan University of Traditional Chinese Medicine, Changsha 410208, China.
| | - Duan-Fang Liao
- Division of Stem Cell Regulation and Application, College of Medicine, Hunan University of Traditional Chinese Medicine, Changsha 410208, China.
| | - Xi-Long Zheng
- Division of Stem Cell Regulation and Application, College of Medicine, Hunan University of Traditional Chinese Medicine, Changsha 410208, China.
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Targeted delivery of miRNA therapeutics for cardiovascular diseases: opportunities and challenges. Clin Sci (Lond) 2014; 127:351-65. [PMID: 24895056 DOI: 10.1042/cs20140005] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Dysregulation of miRNA expression has been associated with many cardiovascular diseases in animal models, as well as in patients. In the present review, we summarize recent findings on the role of miRNAs in cardiovascular diseases and discuss the opportunities, possibilities and challenges of using miRNAs as future therapeutic targets. Furthermore, we focus on the different approaches that can be used to deliver these newly developed miRNA therapeutics to their sites of action. Since siRNAs are structurally homologous with the miRNA therapeutics, important lessons learned from siRNA delivery strategies are discussed that might be applicable to targeted delivery of miRNA therapeutics, thereby reducing costs and potential side effects, and improving efficacy.
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Small molecules, big effects: the role of microRNAs in regulation of cardiomyocyte death. Cell Death Dis 2014; 5:e1325. [PMID: 25032848 PMCID: PMC4123081 DOI: 10.1038/cddis.2014.287] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 05/28/2014] [Accepted: 06/03/2014] [Indexed: 01/14/2023]
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs involved in posttranscriptional regulation of gene expression, and exerting regulatory roles in plethora of biological processes. In recent years, miRNAs have received increased attention for their crucial role in health and disease, including in cardiovascular disease. This review summarizes the role of miRNAs in regulation of cardiac cell death/cell survival pathways, including apoptosis, autophagy and necrosis. It is envisaged that these miRNAs may explain the mechanisms behind the pathogenesis of many cardiac diseases, and, most importantly, may provide new avenues for therapeutic intervention that will limit cardiomyocyte cell death before it irreversibly affects cardiac function. Through an in-depth literature analysis coupled with integrative bioinformatics (pathway and synergy analysis), we dissect here the landscape of complex relationships between the apoptosis-regulating miRNAs in the context of cardiomyocyte cell death (including regulation of autophagy–apoptosis cross talk), and examine the gaps in our current understanding that will guide future investigations.
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miRNA Expression in Mesenchymal Stem Cells. CURRENT PATHOBIOLOGY REPORTS 2014. [DOI: 10.1007/s40139-014-0045-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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Lee SM, Choi H, Yang G, Park KC, Jeong S, Hong S. microRNAs mediate oleic acid-induced acute lung injury in rats using an alternative injury mechanism. Mol Med Rep 2014; 10:292-300. [PMID: 24736893 DOI: 10.3892/mmr.2014.2155] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 03/17/2014] [Indexed: 11/06/2022] Open
Abstract
Intravenous (IV) infusion of oleic acid (OA) distributes OA microemboli in the pulmonary capillaries, which results in severe vascular congestion, hemorrhage vascular congestion, interstitial edema, intravascular coagulation and bleeding. The immune response to acute lung injury (ALI) is known to be associated with rapid and widespread changes in microRNA (miRNA) expression in the lung. The present study of a model of rat lung injury aimed to investigate how the lung miRNA profile changes to mediate ALI. For the induction of ALI, OA (200 µl/kg) suspended in 20% ethyl alcohol was injected through the tail vein for 20 min. Lung tissue samples were acquired at 3, 6 and 24 h, and miRNA microarray and quantitative polymerase chain reaction were performed using these samples. The activation of phosphatase and tensin homolog (PTEN), protein kinase B (Akt), extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK) were analyzed by western blot analysis. There were 75 miRNAs that demonstrated >1.5‑fold changes in expression levels. miR-101a was highly upregulated at 3 h. miR-21 was upregulated in the OA group throughout the 24 h following OA challenge. miR-1 was the most downregulated miRNA at 24 h. In order to examine the expression levels of PTEN and Akt as targets of miR-21, western blot analysis was performed. At 3 h, the levels of PTEN were attenuated in the OA group as compared with those in the control group; however, p-Akt/Akt levels were increased at 3 h for the OA group. PTEN and p-Akt/Akt were significantly higher in the OA group at 3 h and were rapidly decreased at 6 h. The immunohistochemical stain of α-smooth muscle actin in the bronchial and alveolar wall increased 24 h after OA‑induced ALI. These results indicated that the profile of miRNAs dynamically changed throughout the OA-induced ALI process, and mitogen-activated protein kinase activation, PTEN/Akt pathway alteration and smooth muscle actin activation were observed in this ALI model.
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Affiliation(s)
- Sang Mook Lee
- Department of Anaesthesia and Pain Medicine, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 137‑701, Republic of Korea
| | - Hyunsoo Choi
- Clinical Research Institute, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 137‑701, Republic of Korea
| | - Geumjin Yang
- Clinical Research Institute, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 137‑701, Republic of Korea
| | - Ki Cheol Park
- Clinical Research Institute, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 137‑701, Republic of Korea
| | - Sikyoung Jeong
- Department of Emergency Medicine, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 137‑701, Republic of Korea
| | - Sungyoup Hong
- Department of Emergency Medicine, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 137‑701, Republic of Korea
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Seok HY, Chen J, Kataoka M, Huang ZP, Ding J, Yan J, Hu X, Wang DZ. Loss of MicroRNA-155 protects the heart from pathological cardiac hypertrophy. Circ Res 2014; 114:1585-95. [PMID: 24657879 DOI: 10.1161/circresaha.114.303784] [Citation(s) in RCA: 138] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
RATIONALE In response to mechanical and pathological stress, adult mammalian hearts often undergo mal-remodeling, a process commonly characterized as pathological hypertrophy, which is associated with upregulation of fetal genes, increased fibrosis, and reduction of cardiac dysfunction. The molecular pathways that regulate this process are not fully understood. OBJECTIVE To explore the function of microRNA-155 (miR-155) in cardiac hypertrophy and remodeling. METHODS AND RESULTS Our previous work identified miR-155 as a critical microRNA that repressed the expression and function of the myocyte enhancer factor 2A. In this study, we found that miR-155 is expressed in cardiomyocytes and that its expression is reduced in pressure overload-induced hypertrophic hearts. In mouse models of cardiac hypertrophy, miR-155 null hearts suppressed cardiac hypertrophy and cardiac remodeling in response to 2 independent pathological stressors, transverse aortic restriction and an activated calcineurin transgene. Most importantly, loss of miR-155 prevents the progress of heart failure and substantially extends the survival of calcineurin transgenic mice. The function of miR-155 in hypertrophy is confirmed in isolated cardiomyocytes. We identified jumonji, AT rich interactive domain 2 (Jarid2) as an miR-155 target in the heart. miR-155 directly represses Jarid2, whose expression is increased in miR-155 null hearts. Inhibition of endogenous Jarid2 partially rescues the effect of miR-155 loss in isolated cardiomyocytes. CONCLUSIONS Our studies uncover miR-155 as an inducer of pathological cardiomyocyte hypertrophy and suggest that inhibition of endogenous miR-155 might have clinical potential to suppress cardiac hypertrophy and heart failure.
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Affiliation(s)
- Hee Young Seok
- From the Department of Cardiology, Boston Children's Hospital, Harvard Medical School, MA (H.Y.S., J.C., M.K., Z.-P.H., J.D., J.Y., X.H., D.-Z.W.); Program of Integrative Medicine, Department of Cardiology, Beijing University of Chinese Medicine, Beijing, China (J.Y.); and Harvard Stem Cell Institute, Harvard University, Cambridge, MA (D.-Z.W.)
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Wang K, Liu F, Zhou LY, Long B, Yuan SM, Wang Y, Liu CY, Sun T, Zhang XJ, Li PF. The long noncoding RNA CHRF regulates cardiac hypertrophy by targeting miR-489. Circ Res 2014; 114:1377-88. [PMID: 24557880 DOI: 10.1161/circresaha.114.302476] [Citation(s) in RCA: 465] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
RATIONALE Sustained cardiac hypertrophy is often accompanied by maladaptive cardiac remodeling leading to decreased compliance and increased risk for heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have various biological functions and have been extensively investigated in past years. OBJECTIVE We identified miR-489 and lncRNAs (cardiac hypertrophy related factor, CHRF) from hypertrophic cardiomyocytes. Here, we tested the hypothesis that miR-489 and CHRF can participate in the regulation of cardiac hypertrophy in vivo and in vitro. METHODS AND RESULTS A microarray was performed to analyze miRNAs in response to angiotensin II treatment, and we found miR-489 was substantially reduced. Enforced expression of miR-489 in cardiomyocytes and transgenic overexpression of miR-489 both exhibited reduced hypertrophic response on angiotensin II treatment. We identified myeloid differentiation primary response gene 88 (Myd88) as a miR-489 target to mediate the function of miR-489 in cardiac hypertrophy. Knockdown of Myd88 in cardiomyocytes and Myd88-knockout mice both showed attenuated hypertrophic responses. Furthermore, we explored the molecular mechanism by which miR-489 expression is regulated and found that an lncRNA that we named CHRF acts as an endogenous sponge of miR-489, which downregulates miR-489 expression levels. CHRF is able to directly bind to miR-489 and regulate Myd88 expression and hypertrophy. CONCLUSIONS Our present study reveals a novel cardiac hypertrophy regulating model that is composed of CHRF, miR-489, and Myd88. The modulation of their levels may provide a new approach for tackling cardiac hypertrophy.
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Affiliation(s)
- Kun Wang
- From the Division of Cardiovascular Research, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
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Moldovan L, Batte KE, Trgovcich J, Wisler J, Marsh CB, Piper M. Methodological challenges in utilizing miRNAs as circulating biomarkers. J Cell Mol Med 2014; 18:371-90. [PMID: 24533657 PMCID: PMC3943687 DOI: 10.1111/jcmm.12236] [Citation(s) in RCA: 319] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Accepted: 12/18/2013] [Indexed: 01/06/2023] Open
Abstract
MicroRNAs (miRNAs) have emerged as important regulators in the post-transcriptional control of gene expression. The discovery of their presence not only in tissues but also in extratissular fluids, including blood, urine and cerebro-spinal fluid, together with their changes in expression in various pathological conditions, has implicated these extracellular miRNAs as informative biomarkers of disease. However, exploiting miRNAs in this capacity requires methodological rigour. Here, we report several key procedural aspects of miRNA isolation from plasma and serum, as exemplified by research in cardiovascular and pulmonary diseases. We also highlight the advantages and disadvantages of various profiling methods to determine the expression levels of plasma- and serum-derived miRNAs. Attention to such methodological details is critical, as circulating miRNAs become diagnostic tools for various human diseases.
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Affiliation(s)
- Leni Moldovan
- Division of Pulmonary, Allergy, Critical Care, Sleep Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA
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Chaulk SG, Xu Z, Glover MJN, Fahlman RP. MicroRNA miR-92a-1 biogenesis and mRNA targeting is modulated by a tertiary contact within the miR-17~92 microRNA cluster. Nucleic Acids Res 2014; 42:5234-44. [PMID: 24520115 PMCID: PMC4005684 DOI: 10.1093/nar/gku133] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
While functional mature microRNAs (miRNAs) are small ∼22 base oligonucleotides that target specific mRNAs, miRNAs are initially expressed as long transcripts (pri-miRNAs) that undergo sequential processing to yield the mature miRNAs. We have previously reported that the pri-miR-17∼92 cluster adopts a compact globular folded structure that internalizes a 3' core domain resulting in reduced miRNA maturation and subsequent mRNA targeting. Using a site-specific photo-cross-linker we have identified a tertiary contact within the 3' core domain of the pri-miRNA between a non-miRNA stem-loop and the pre-miR-19b hairpin. This tertiary contact is involved in the formation of the compact globular fold of the cluster while its disruption enhances miR-92a expression and mRNA targeting. We propose that this tertiary contact serves as a molecular scaffold to restrict expression of the proposed antiangiogenic miR-92a, allowing for the overall pro-angiogenic effect of miR-17∼92 expression.
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Affiliation(s)
- Steven G Chaulk
- Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada and Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada
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Baars T, Skyschally A, Klein-Hitpass L, Cario E, Erbel R, Heusch G, Kleinbongard P. microRNA expression and its potential role in cardioprotection by ischemic postconditioning in pigs. Pflugers Arch 2014; 466:1953-61. [DOI: 10.1007/s00424-013-1429-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 12/19/2013] [Indexed: 12/22/2022]
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