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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.
AuthorsYang Zhang, Xiao-Ru Huang, Li-Hua Wei, Arthur Ck Chung, Cheuk-Man Yu, Hui-Yao Lan
JournalMolecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 22 Issue 5 Pg. 974-85 (May 2014) ISSN: 1525-0024 [Electronic] United States
PMID24569834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • MIRN29a microRNA, human
  • MicroRNAs
  • SMAD3 protein, human
  • Smad3 Protein
  • Transforming Growth Factor beta
  • Angiotensin II
Topics
  • Angiotensin II (toxicity)
  • Animals
  • Disease Models, Animal
  • Endomyocardial Fibrosis (chemically induced, genetics, therapy)
  • Gene Expression Regulation (genetics)
  • Gene Knockdown Techniques
  • Humans
  • Hypertension (chemically induced, genetics, therapy)
  • Mice
  • MicroRNAs (antagonists & inhibitors, biosynthesis, genetics)
  • Molecular Targeted Therapy
  • Signal Transduction (genetics)
  • Smad3 Protein (antagonists & inhibitors, genetics, metabolism)
  • Transforming Growth Factor beta (antagonists & inhibitors, genetics, metabolism)

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