Abstract 408: Myocardial Knockdown of Mir-375 Attenuates Post-mi Inflammatory Response and Left Ventricular Dysfunction via Pdk-1-akt Signaling Axis
MicroRNAs are known to be dysregulated in the ischemic heart disease and have emerged as potential therapeutic targets for treatment of myocardial infarction (MI). Recently MicroRNA-375 has been shown to be up-regulated in humans with MI. In this study, we assessed whether inhibition of the miR-375 using an i.v.-delivered locked nucleic acid (LNA)-modified anti-miR (LNA-antimiR-375) can provide therapeutic benefit in mice with pre-existing pathological cardiac remodeling and dysfunction due to myocardial infarction (MI).After the induction of acute myocardial infarction, mice were treated with either control or LNA based miR-375 inhibitor, and inflammatory response, cardiomyocyte apoptosis and LV functional and structural remodeling changes were evaluated. Anti-miR-375 therapy significantly suppressed infiltration of inflammatory cells, expression of proinflammatory cytokines in the myocardium and cardiomyocyte apoptosis. These changes were associated with miR-375 mediated activation of 3-phosphoinositide-dependent protein kinase 1 (PDK-1) and downstream AKT phosphorylation on Thr-308. LNA anti-miR-375 therapy significantly improved LV functions, reduced infarct size, and attenuated infarct wall thinning. Moreover, LNA based miR-375 therapy significantly increased capillary density in the infarcted myocardium. Further, our in vitro studies demonstrated that miR-375 negatively regulates the expression of PDK-1 by directly targeting the 3’UTR of the PDK-1 transcript. Taken together, our studies demonstrate that anti miR-375 therapy suppresses inflammatory response, cardiomyocyte death and contributes to improved LV function and enhanced angiogenesis via activation of PDK-1/AKT signaling.
Author Disclosures: V.N. Garikipati: None. S.K. Verma: None. M. Khan: None. A.M. Gumpert: None. J. Zhou: None. Z. Cheng: None. C. Benedict: None. E. Nickoloff: None. J. Johnson: None. A. Yuan: None. E. Gao: None. R. Kishore: None.
This research has received full or partial funding support from the American Heart Association, Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).
- © 2015 by American Heart Association, Inc.