title: Attenuation of microRNA-16 derepresses the cyclins D1, D2 and E1 to provoke cardiomyocyte hypertrophy.
abstract: Cyclins/retinoblastoma protein (pRb) pathway participates in cardiomyocyte hypertrophy. MicroRNAs (miRNAs), the endogenous small non-coding RNAs, were recognized to play significant roles in cardiac hypertrophy. But, it remains unknown whether cyclin/Rb pathway is modulated by miRNAs during cardiac hypertrophy. This study investigates the potential role of microRNA-16 (miR-16) in modulating cyclin/Rb pathway during cardiomyocyte hypertrophy. An animal model of hypertrophy was established in a rat with abdominal aortic constriction (AAC), and in a mouse with transverse aortic constriction (TAC) and in a mouse with subcutaneous injection of phenylephrine (PE) respectively. In addition, a cell model of hypertrophy was also achieved based on PE-promoted neonatal rat ventricular cardiomyocyte and based on Ang-II-induced neonatal mouse ventricular cardiomyocyte respectively. We demonstrated that miR-16 expression was markedly decreased in hypertrophic myocardium and hypertrophic cardiomyocytes in rats and mice. Overexpression of miR-16 suppressed rat cardiac hypertrophy and hypertrophic phenotype of cultured cardiomyocytes, and inhibition of miR-16 induced a hypertrophic phenotype in cardiomyocytes. Expressions of cyclins D1, D2 and E1, and the phosphorylated pRb were increased in hypertrophic myocardium and hypertrophic cardiomyocytes, but could be reversed by enforced expression of miR-16. Cyclins D1, D2 and E1, not pRb, were further validated to be modulated post-transcriptionally by miR-16. In addition, the signal transducer and activator of transcription-3 and c-Myc were activated during myocardial hypertrophy, and inhibitions of them prevented miR-16 attenuation. Therefore, attenuation of miR-16 provoke cardiomyocyte hypertrophy via derepressing the cyclins D1, D2 and E1, and activating cyclin/Rb pathway, revealing that miR-16 might be a target to manage cardiac hypertrophy.
authors.affiliation: Medical Research Department of Guangdong General Hospital, Guangdong Provincial Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Huang
authors.forename: Xiao
authors.initials: X
authors.lastname: Zou
authors.forename: Jie-Ning
authors.initials: JN
authors.lastname: Zhu
authors.forename: Yong-Heng
authors.initials: YH
authors.lastname: Fu
authors.forename: Qiu-Xiong
authors.initials: QX
authors.lastname: Lin
authors.forename: Ye-You
authors.initials: YY
authors.lastname: Liang
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Deng
authors.forename: Su-Juan
authors.initials: SJ
authors.lastname: Kuang
authors.forename: Meng-Zhen
authors.initials: MZ
authors.lastname: Zhang
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Liao
authors.forename: Xi-Long
authors.initials: XL
authors.lastname: Zheng
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Shan
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D006332:Cardiomegaly / Q000235:genetics*; D002460:Cell Line; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism*; D056742:Cyclin D2 / Q000096:biosynthesis / Q000378:metabolism*; D016213:Cyclins / Q000096:biosynthesis / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000473:pathology; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc; D051381:Rats; D017207:Rats, Sprague-Dawley; D016160:Retinoblastoma Protein / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: C530106:Ccnd1 protein, rat; C486197:Ccnd2 protein, rat; D056742:Cyclin D2; D016213:Cyclins; C547573:MIRN16 microRNA, rat; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C583044:cyclin E1, rat; D019938:Cyclin D1; D010656:Phenylephrine
keywords: cardiac hypertrophy; cardiomyocyte; cyclin; microRNA-16; retinoblastoma protein