Abstract 17085: MicroRNA-24 Prevents Apoptosis and Preserves Cardiac Function after Myocardial Infarction Through Cell-Autonomous Effects in Cardiomyocytes

Abstract

Background Apoptosis due to myocardial infarction (MI) leads to an irreversible loss of cardiomyocytes. MicroRNAs may influence this process by post-transcriptionally regulating the expression of proteins involved in apoptotic pathways. We have previously shown that exogenous application of miR-24 after coronary artery ligation in mice preserves cardiac function by repressing the pro-apoptotic protein Bim. Here, we investigate whether miR-24 delivered by local injection exerts its effects primarily within cardiomyocytes or non-cell autonomously through neighboring cells. Methods We genetically targeted miR-24 under control of the cardiac-specific Myh6 promoter, and selected a line of transgenic mice (αMHC-miR-24 mice) with six fold greater expression of miR-24 than control littermates. MI was induced by coronary artery ligation. Apoptosis and infarct size were quantified with TUNEL assays (n=16) and AZAN staining (n=15) 24 hours and 4 weeks post-MI, respectively. Cardiac function was measured by high-resolution echocardiography at baseline and 3 days and 4 weeks post-MI (n=42). QRT-PCR and Western blotting were performed on cardiac tissue 24 hours post-MI (n=6). Results αMHC-miR-24 mice were protected against apoptosis after MI compared to wildtype littermates as indicated by reduced numbers of TUNEL-positive cardiomyocytes in the ischemic zone and border zone compared to wildtype littermates. Cardiac function was preserved (Ejection fraction 55.0 ± 0.9 vs. 56.9 ± 0.9 % at baseline, p=NS, 32.8 ± 1.7 vs. 28.1 ± 1.6% at 3 days, p<0.05, 26.7 ± 1.9 vs. 21.9 ± 1.4% at 4 weeks, p<0.05; Fractional shortening 32.9 ± 1.1 vs. 32.5 ± 1.1% at baseline, 15.1 ± 0.5 vs 12.6 ± 0.08% at 3 days, p<0.05, 15.0 ± 0.9 vs. 12.0 ± 0.7% at 4 weeks, p<0.05). Hearts of αMHC-miR-24 mice exhibited lower levels of Bim protein, lower levels of stress markers such as ANF and BNP and partially restored levels of dysregulated miRNAs 19a, 195 and 208, similar to miR-24 mimic injection in the heart. Conclusion The similarity between the effects of local delivery and cardiomyocyte-specific overexpression of miR-24 provides evidence that miR-24 improves left ventricular function after myocardial infarction by cell autonomously inhibiting cardiomyocyte death.