title: E2F1-regulated miR-30b suppresses Cyclophilin D and protects heart from ischemia/reperfusion injury and necrotic cell death.
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.
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: K
authors.initials: K
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: T
authors.initials: T
authors.lastname: An
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: L-Y
authors.initials: LY
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: X-J
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: C
authors.initials: C
authors.lastname: Feng
authors.affiliation: Center for Developmental Cardiology, Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
authors.forename: P-F
authors.initials: PF
authors.lastname: Li
mesh_terms: D000818:Animals; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D015398:Signal Transduction
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D035683:MicroRNAs; C534715:Mirn30d microRNA, mouse; C000631446:PPIF protein, mouse; D021983:Cyclophilins