Abstract 294: Therapeutic Silencing of miR-375 Attenuates Post-MI Inflammatory Response and Left Ventricular Dysfunction in Mice With Myocardial Infarction

Abstract

MicroRNAs are known to be dysregulated in the ischemic heart disease and have emerged as potential therapeutic targets for treatment of myocardial infarction (MI). Our preliminary data indicated elevated MicroRNA-375 levels in failing human heart tissue. Therefore, we assessed whether inhibition of the miR-375 using a s.c.-delivered locked nucleic acid (LNA)-modified anti-miR (LNA-antimiR-375) can provide therapeutic benefit in mice with myocardial infarction (MI). After the induction of acute myocardial infarction, mice were treated with either control or LNA based LNA-anti-miR-375, and inflammatory response, cardiomyocyte apoptosis, capillary density and LV functional and structural remodeling changes were evaluated. LNA-anti-miR-375 therapy significantly reduced inflammatory cell infiltration, expression of pro-inflammatory cytokines and cardiomyocyte apoptosis in the myocardium. Further, our cell sorting experiments revealed that within the myocardium, LNA-anti-miR-375 was taken up by cardiomyocytes, endothelial cells and macrophages and repressed miR-375 levels, thereby activating 3-phosphoinositide-dependent protein kinase 1 (PDK-1) and downstream AKT phosphorylation on Thr-308. LNA anti-miR-375 therapy significantly improved LV functions, enhanced neovascularization and reduced infarct size. Corroborating with our in vivo findings, our in vitro studies demonstrated that knock down of miR-375 in macrophages enhanced the expression of PDK-1 and revealed reduced pro-inflammatory cytokines expression following LPS challenge. Taken together, our studies demonstrate that anti miR-375 therapy reduced inflammatory response, cardiomyocyte death, improved LV function and enhanced angiogenesis by targeting multiple cell types via activation of PDK-1/AKT signaling.