Abstract 3830: MicroRNA-21 Derepresses MAPkinase-Signaling and its Antagonism Prevents Cardiac Failure
MicroRNAs (miRNAs) are endogenous small RNA molecules that negatively regulate the expression of complementary target messenger RNAs. Using microarray-based miRNA expression analysis, we identified miR-21 as the strongest upregulated miRNA in murine hypertrophic myocardium after transaortic constriction (TAC) and failing human hearts. Transgene animals overexpression miR-21 specifically in cardiomyocytes did not present any cardiac pathologies during aging. In addition, the decline in cardiac function after pressure-overload was similar in miR-21 transgenes and wildtype contros. In contrast to cardiomyocytes, miR-21 was mainly expressed in cardiac fibroblasts. MiR-21 levels were increased in the failing heart and augmented ERK-MAPkinase activity through inhibition of the direct miR21-target sprouty1 (Spry1). This mechanism appeared to regulate fibroblast survival and growth factor secretion and to control the extent and severity of interstitial fibrosis and hypertrophy. We developed an in vivo delivery model for cholesterol-bound miRNA antagonists (“antagomirs”). In vivo silencing of miR-21 by a specific antagomir in a murine pressure overload-induced disease model reduced cardiac ERK-MAPkinase activity, prevented interstitial fibrosis and attenuated cardiac dysfunction. Myocyte cross-sectional area was significantly increased in placebo-treated animals but close to normal in antagomir-21 treated mice. Global transcriptome analysis revealed reexpression of a fetal gene program and activation of genes implicated in collagen turnover after TAC, which was prevented by antagomir-based knockdown of cardiac miR-21. Indeed, antagomir-21 treated animals displayed significantly less cardiac fibrosis. These findings validate miR-21 as a disease target in heart failure and for the first time establish the therapeutic efficacy for a microRNA therapeutic intervention in a cardiovascular disease setting.