title: miR-34a modulates angiotensin II-induced myocardial hypertrophy by direct inhibition of ATG9A expression and autophagic activity.
abstract: Cardiac hypertrophy is characterized by thickening myocardium and decreasing in heart chamber volume in response to mechanical or pathological stress, but the underlying molecular mechanisms remain to be defined. This study investigated altered miRNA expression and autophagic activity in pathogenesis of cardiac hypertrophy. A rat model of myocardial hypertrophy was used and confirmed by heart morphology, induction of cardiomyocyte autophagy, altered expression of autophagy-related ATG9A, LC3 II/I and p62 proteins, and decrease in miR-34a expression. The in vitro data showed that in hypertrophic cardiomyocytes induced by Ang II, miR-34a expression was downregulated, whereas ATG9A expression was up-regulated. Moreover, miR-34a was able to bind to ATG9A 3'-UTR, but not to the mutated 3'-UTR and inhibited ATG9A protein expression and autophagic activity. The latter was evaluated by autophagy-related LC3 II/I and p62 levels, TEM, and flow cytometry in rat cardiomyocytes. In addition, ATG9A expression induced either by treatment of rat cardiomyocytes with Ang II or ATG9A cDNA transfection upregulated autophagic activity and cardiomyocyte hypertrophy in both morphology and expression of hypertrophy-related genes (i.e., ANP and β-MHC), whereas knockdown of ATG9A expression downregulated autophagic activity and cardiomyocyte hypertrophy. However, miR-34a antagonized Ang II-stimulated myocardial hypertrophy, whereas inhibition of miR-34a expression aggravated Ang II-stimulated myocardial hypertrophy (such as cardiomyocyte hypertrophy-related ANP and β-MHC expression and cardiomyocyte morphology). This study indicates that miR-34a plays a role in regulation of Ang II-induced cardiomyocyte hypertrophy by inhibition of ATG9A expression and autophagic activity.
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: Jionghua
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: Chuanfang
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: You
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: Benrong
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: Longgen
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Institute of Cardiovascular Disease, Guangzhou, China.
authors.forename: Shiming
authors.initials: S
authors.lastname: Liu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D001483:Base Sequence; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D034741:RNA, Small Interfering / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013599:Systole / Q000187:drug effects; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure
chemical_list: C000594371:ATG9A protein, rat; C560944:MIRN34 microRNA, rat; D008565:Membrane Proteins; D035683:MicroRNAs; D034741:RNA, Small Interfering; D000804:Angiotensin II
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