Journal Article

miR-29b as a Therapeutic Agent for Angiotensin II-induced Cardiac Fibrosis by Targeting TGF-β/Smad3 signaling

Yu, Cheuk-Man, Lan, Hui-Yao, Zhang, Yang, Huang, Xiao-Ru, Wei, Li-Hua, Chung, Arthur CK

2014

Overview

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.

• Publisher: Elsevier Inc,Nature Publishing Group
• Subject: Angiotensin II - toxicity / Animals / Disease Models, Animal / Endomyocardial Fibrosis - chemically induced / Endomyocardial Fibrosis - genetics / Endomyocardial Fibrosis - therapy / Gene Expression Regulation - genetics / Gene Knockdown Techniques / Humans / Hypertension - chemically induced / Hypertension - genetics / Hypertension - therapy / Mice / MicroRNAs - antagonists & inhibitors / MicroRNAs - biosynthesis / MicroRNAs - genetics / Molecular Targeted Therapy / Original / Signal Transduction - genetics / Smad3 Protein - antagonists & inhibitors / Smad3 Protein - genetics / Smad3 Protein - metabolism / Transforming Growth Factor beta - antagonists & inhibitors / Transforming Growth Factor beta - genetics / Transforming Growth Factor beta - metabolism