title: Suppression of Bim by microRNA-19a may protect cardiomyocytes against hypoxia-induced cell death via autophagy activation.
abstract: Microvascular obstruction (MO), one of unfavorable complications of percutaneous coronary intervention (PCI), is responsible for the lost benefit of reperfusion therapy. Determination of microRNA-19a, a member of the miR-17-92 cluster, using quantitative real-time polymerase chain reaction (PCR) revealed notably down-regulated microRNA-19a, in myocardium with MO. Nonetheless, the role of miR-19a in MO and the underlying mechanism remains to be elucidated. To this end, an in vitro microembolization model in cardiomyocytes was used. Our data revealed that hypoxic exposure prompted cardiomyocyte apoptosis in a time-dependent manner accompanied by reduced miR-19a. miR-19a overexpression clearly ameliorated hypoxia-induced cell death (necrosis and apoptosis), at least in part, through switching on autophagy. Further dual-luciferase reporter assay and immunoblotting studies demonstrated that miR-19a-induced cytoprotection might be achieved in part through modulation of the specific target Bcl-2 interacting mediator of cell death, Bim, an apoptotic activator. Bim sufficiently interfered with miR-19a-induced LC3 conversion and increased cardiomyocyte apoptosis under hypoxia. Moreover, cardiomyocytes pretreated with 3-methyladenine conferred resistance to the cytoprotective effect of miR-19a and displayed notably increased TUNEL staining and caspase-3 activity. In conclusion, miR-19a protected cardiomyocytes against hypoxia-induced lethality at least in part via Bim suppression and subsequently autophagy activation.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Gao
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: qian.juying@zs-hospital.sh.cn.
authors.forename: Ju-Ying
authors.initials: JY
authors.lastname: Qian
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Zhang-Wei
authors.initials: ZW
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Fu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Xu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Ding
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Yang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Cao
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Yun-Zeng
authors.initials: YZ
authors.lastname: Zou
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China; University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Ai-Jun
authors.initials: AJ
authors.lastname: Sun
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: jbge@zs-hospital.sh.cn.
authors.forename: Jun-Bo
authors.initials: JB
authors.lastname: Ge
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001343:Autophagy; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D015687:Cell Hypoxia; D002478:Cells, Cultured; D015536:Down-Regulation; D017930:Genes, Reporter; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; C586754:MIRN19 microRNA, rat; D035683:MicroRNAs
keywords: Apoptosis; Autophagy; Bim; Cardiomyocytes; Hypoxia; MiR-19a