title: Crucial Role of miR-433 in Regulating Cardiac Fibrosis.
abstract: Dysregulation of microRNAs has been implicated in many cardiovascular diseases including fibrosis. Here we report that miR-433 was consistently elevated in three models of heart disease with prominent cardiac fibrosis, and was enriched in fibroblasts compared to cardiomyocytes. Forced expression of miR-433 in neonatal rat cardiac fibroblasts increased proliferation and their differentiation into myofibroblasts as determined by EdU incorporation, α-SMA staining, and expression levels of fibrosis-associated genes. Conversely, inhibition of miR-433 exhibited opposite results. AZIN1 and JNK1 were identified as two target genes of miR-433. Decreased level of AZIN1 activated TGF-β1 while down-regulation of JNK1 resulted in activation of ERK and p38 kinase leading to Smad3 activation and ultimately cardiac fibrosis. Importantly, systemic neutralization of miR-433 or adeno-associated virus 9 (AAV9)-mediated cardiac transfer of a miR-433 sponge attenuated cardiac fibrosis and ventricular dysfunction following myocardial infarction. Thus, our work suggests that miR-433 is a potential target for amelioration of cardiac fibrosis.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Lichan
authors.initials: L
authors.lastname: Tao
authors.affiliation: Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai 200444, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Bei
authors.affiliation: Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai 200444, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Laboratory of Experimental Cardiology, University Medical Centre Utrecht, Utrecht 3508GA, The Netherlands.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Lei
authors.affiliation: Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai 200444, China.
authors.forename: Siyi
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Che
authors.affiliation: Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.affiliation: Laboratory of Experimental Cardiology, University Medical Centre Utrecht, Utrecht 3508GA, The Netherlands.
authors.forename: Joost Pg
authors.initials: JP
authors.lastname: Sluijter
authors.affiliation: Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Saumya
authors.initials: S
authors.lastname: Das
authors.affiliation: Victor Babes National Institute of Pathology, Bucharest 050096, Romania.; Division of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest 050474, Romania.
authors.forename: Dragos
authors.initials: D
authors.lastname: Cretoiu
authors.affiliation: Innovative Drug Research Center of Shanghai University, Shanghai 200444, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Medical Genomics & Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jiuchang
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Cardiac Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai 200444, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005355:Fibrosis / Q000473:pathology*; D020869:Gene Expression Profiling; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D032446:Myoblasts / Q000502:physiology; D009203:Myocardial Infarction / Q000150:complications* / Q000473:pathology*; D051381:Rats
chemical_list: D035683:MicroRNAs; C533108:Mirn433 microRNA, mouse
keywords: AZIN1; JNK1.; cardiac fibrosis; miR-433