title: Attenuation of microRNA-1 derepresses the cytoskeleton regulatory protein twinfilin-1 to provoke cardiac hypertrophy.
abstract: MicroRNAs are involved in several aspects of cardiac hypertrophy, including cardiac growth, conduction, and fibrosis. However, their effects on the regulation of the cardiomyocyte cytoskeleton in this pathological process are not known. Here, with microRNA microarray and small RNA library sequencing, we show that microRNA-1 (miR-1) is the most abundant microRNA in the human heart. By applying bioinformatic target prediction, a cytoskeleton regulatory protein twinfilin-1 was identified as a potential target of miR-1. Overexpression of miR-1 not only reduced the luciferase activity of the reporter containing the 3' untranslated region of twinfilin-1 mRNA, but also suppressed the endogenous protein expression of twinfilin-1, indicating that twinfilin-1 is a direct target of miR-1. miR-1 was substantially downregulated in the rat hypertrophic left ventricle and phenylephrine-induced hypertrophic cardiomyocytes, and accordingly, the protein level of twinfilin-1 was increased. Furthermore, overexpression of miR-1 in hypertrophic cardiomyocytes reduced the cell size and attenuated the expression of hypertrophic markers, whereas silencing of miR-1 in cardiomyocytes resulted in the hypertrophic phenotype. In accordance, twinfilin-1 overexpression promoted cardiomyocyte hypertrophy. Taken together, our results demonstrate that the cytoskeleton regulatory protein twinfilin-1 is a novel target of miR-1, and that reduction of miR-1 by hypertrophic stimuli induces the upregulation of twinfilin-1, which in turn evokes hypertrophy through the regulation of cardiac cytoskeleton.
authors.affiliation: Key Laboratory of Stem Cell Biology and Laboratory of Nucleic Acid and Molecular Medicine, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China. qjing@sibs.ac.cn
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Song
authors.forename: Jun
authors.initials: J
authors.lastname: Zou
authors.forename: Guo-Kun
authors.initials: GK
authors.lastname: Wang
authors.forename: Elena
authors.initials: E
authors.lastname: Kremneva
authors.forename: Xiang-Qi
authors.initials: XQ
authors.lastname: Li
authors.forename: Ni
authors.initials: N
authors.lastname: Zhu
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.forename: Pekka
authors.initials: P
authors.lastname: Lappalainen
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Yuan
authors.forename: Yong-Wen
authors.initials: YW
authors.lastname: Qin
authors.forename: Qing
authors.initials: Q
authors.lastname: Jing
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D003599:Cytoskeleton / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D041681:NIH 3T3 Cells; D010656:Phenylephrine / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019076:Transgenes / Q000235:genetics
chemical_list: C544547:MIRN1 microRNA, human; D035683:MicroRNAs; D008840:Microfilament Proteins; C485188:TWF1 protein, human; D010656:Phenylephrine; D011505:Protein-Tyrosine Kinases