title: MicroRNA-214 Mediates Isoproterenol-induced Proliferation and Collagen Synthesis in Cardiac Fibroblasts.
abstract: The action of β-adrenergic receptors (β-ARs) induces cardiac fibroblast (CF) proliferation and collagen synthesis and is a major source of the cardiac fibrosis caused by various diseases. Recently, microRNA-214 (miR-214) was found to play an important role in the pathogenesis of cardiac remodelling. In the present study, we examined the role and the underlying mechanism of miR-214 in isoproterenol (ISO, a β-AR agonist)-induced CF proliferation and collagen synthesis. The expression of miR-214 was increased in both ISO-mediated fibrotic heart tissue and fibroblasts. Downregulation of miR-214 by antagonists attenuated the proliferation and collagen synthesis in ISO-treated CFs. Using bioinformatics analysis and luciferase assays, mitofusin2 (Mfn2), a critical regulator of cell proliferation and tissue fibrosis, was identified as a direct target gene of miR-214; this result was confirmed by western blot analysis. Additionally, corresponding to the upregulation of miR-214, the expression of Mfn2 was downregulated in the fibrotic heart and fibroblasts. Furthermore, the downregulation of miR-214 inhibited the activation of ERK1/2 MAPK signalling induced by ISO treatment. In conclusion, our study demonstrated that miR-214 mediates CF proliferation and collagen synthesis via inhibition of Mfn2 and activation of ERK1/2 MAPK signalling, which provides a new explanation for the mechanism of β-AR activation-induced cardiac fibrosis.
authors.affiliation: Department of Cardiology, Peking University Third Hospital and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research Beijing 100191, China.
authors.forename: Min
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Peking University Third Hospital and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research Beijing 100191, China.
authors.forename: Haiyi
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Peking University Third Hospital and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research Beijing 100191, China.
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Peking University Third Hospital and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research Beijing 100191, China.
authors.forename: Zijian
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cardiology, Peking University Third Hospital and Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis*; D017124:Conserved Sequence / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D020558:GTP Phosphohydrolases; D055785:Gene Knockdown Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009206:Myocardium / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D008565:Membrane Proteins; D035683:MicroRNAs; C559947:Mirn214 microRNA, rat; D024101:Mitochondrial Proteins; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat; D007545:Isoproterenol