title: Cardiomyocyte overexpression of miR-27b induces cardiac hypertrophy and dysfunction in mice.
abstract: Recent studies have begun to reveal critical roles of microRNAs (miRNAs) in the pathogenesis of cardiac hypertrophy and dysfunction. In this study, we tested whether a transforming growth factor-β (TGF-β)-regulated miRNA played a pivotal role in the development of cardiac hypertrophy and heart failure (HF). We observed that miR-27b was upregulated in hearts of cardiomyocyte-specific Smad4 knockout mice, which developed cardiac hypertrophy. In vitro experiments showed that the miR-27b expression could be inhibited by TGF-β1 and that its overexpression promoted hypertrophic cell growth, while the miR-27b suppression led to inhibition of the hypertrophic cell growth caused by phenylephrine (PE) treatment. Furthermore, the analysis of transgenic mice with cardiomyocyte-specific overexpression of miR-27b revealed that miR-27b overexpression was sufficient to induce cardiac hypertrophy and dysfunction. We validated the peroxisome proliferator-activated receptor-γ (PPAR-γ) as a direct target of miR-27b in cardiomyocyte. Consistently, the miR-27b transgenic mice displayed significantly lower levels of PPAR-γ than the control mice. Furthermore, in vivo silencing of miR-27b using a specific antagomir in a pressure-overload-induced mouse model of HF increased cardiac PPAR-γ expression, attenuated cardiac hypertrophy and dysfunction. The results of our study demonstrate that TGF-β1-regulated miR-27b is involved in the regulation of cardiac hypertrophy, and validate miR-27b as an efficient therapeutic target for cardiac diseases.
authors.affiliation: State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, 20 Dongdajie, Beijing 100071, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Yao
authors.initials: Y
authors.lastname: Song
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Han
authors.initials: H
authors.lastname: Xiao
authors.forename: Qiang
authors.initials: Q
authors.lastname: Sun
authors.forename: Ning
authors.initials: N
authors.lastname: Hou
authors.forename: Shuilong
authors.initials: S
authors.lastname: Guo
authors.forename: Youliang
authors.initials: Y
authors.lastname: Wang
authors.forename: Kaiji
authors.initials: K
authors.lastname: Fan
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhan
authors.forename: Lagabaiyila
authors.initials: L
authors.lastname: Zha
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Li
authors.forename: Xuan
authors.initials: X
authors.lastname: Cheng
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051901:Smad4 Protein / Q000172:deficiency / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C540674:Mirn27 microRNA, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta