title: miR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-β/Smad3 signaling.
abstract: Loss of miR-29 is associated with cardiac fibrosis. This study examined the role and therapeutic potential of miR-29 in mouse model of hypertension induced by angiotensin II (AngII). By using microRNA microarray, in situ hybridization, and real-time polymerase chain reaction, we found that AngII-induced cardiac fibrosis in the hypertensive heart and in cultured cardiac fibroblasts were associated with downregulation of miR-29a-c via a Smad3-dependent mechanism. In vitro knockdown of miR-29b enhanced but overexpression of miR-29b inhibited AngII-induced fibrosis, revealing a protective role of miR-29b in cardiac fibrosis in response to AngII. This was further demonstrated in vivo by the ability of overexpressing miR-29b in the mouse heart to prevent AngII-mediated cardiac fibrosis and cardiac dysfunction. Importantly, we also found that restored miR-29b in the established hypertensive heart was capable of blocking progressive cardiac fibrosis and improving cardiac dysfunction, demonstrating a therapeutic potential of miR-29b for chronic heart disease. Further studies revealed that targeting the transforming growth factor (TGF)-β1 coding sequence region, thereby inhibiting TGF-β/Smad3 signaling, could be a new mechanism by which miR-29b inhibited AngII-induced cardiac fibrosis. In conclusion, miR-29b plays a protective role in AngII-mediated cardiac remodeling and may be a therapeutic agent for cardiac fibrosis by targeting the TGF-β/Smad3 pathway.
authors.affiliation: 1] Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China [2] Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China [2] Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.affiliation: 1] Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China [2] Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Wei
authors.affiliation: 1] Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China [2] Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Arthur Ck
authors.initials: AC
authors.lastname: Chung
authors.affiliation: 1] Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China [2] Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Cheuk-Man
authors.initials: CM
authors.lastname: Yu
authors.affiliation: 1] Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China [2] Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hui-Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D004195:Disease Models, Animal; D004719:Endomyocardial Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000628:therapy; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C532045:MIRN29a microRNA, human; D035683:MicroRNAs; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D000804:Angiotensin II