Abstract 9990: Regulation of miR132 in Cardiac Fibroblasts After Ischemia Enhances Angiogenesis and Reduction of Apoptosis by Targeting Sonic Hedgehog
Background: Synthesis of growth factors by cardiac fibroblasts (CF) during myocardiac ischemia plays an important role in maintaining cardiac structure and function. However, the dominant paracrine mediator and it's molecular mechanism in fibroblasts are not clear.
Methods and Results: In vitro, qPCR analysis identified miR-132 which was significantly down-regulated miRNA in infarcted heart and highly expressed in CF. Sonic hedgehog (Shh), as the predicted targeting gene of miR-132, was specifically expressed in CF and markedly increased during ischemia. To analyze the paracrine effect of Shh on angiogenesis, GFP transfected HUVEC were co-cultured with CF. Knock-down of miR-132 (anti-132) in fibroblasts significantly increased Shh, VEGF, MMP-9 and IGF-1 synthesis, concomitant with increased tube formation in comparison with the null vector transfected CF (CON) and miR-132 overexpressing groups (miR-132). Furthermore, 5 days after MI, TUNNEL staining of infarcted heart revealed an anti-apoptosis effect of anti-132 on cardiomyocytes. Mechanisms contributing to the beneficial effect of miR132 knockdown involve activation of smoothened (Smo), the non-canonical signaling pathway. Administration of miR132 antagomir in vivo after MI significantly enhanced angiogenesis, reduced infarction size, and cardiac remodeling in comparison with miR-132 plasmid and CON group (Fig. 1).
Conclusion: Regulation of miR-132 in CF plays an important role in angiogenesis, anti-apoptosis and reduction of cardiac remodeling by targeting Shh.
- © 2011 by American Heart Association, Inc.