Abstract 470: Reactivation of Fetal MicroRNAs Contribute to Dilated Cardiomyopathy

Abstract

Background: Dilated cardiomyopathy (DCM) is the most common cardiomyopathies that often leads to heart failure worldwide. MicroRNAs have emerged as an integral player in regulating diverse biological processes including those in the cardiovascular system. Previously, our lab has shown that the miR-424(322)/503 cluster is highly enriched during early cardiac fate determination and drives cardiomyocyte specification. However, the expression level of miR-424(322)/503 gradually decreases in the postnatal heart. Other studies have revealed the upregulation of miR-424(322)/503 in failing human hearts. Nevertheless, the association between miR-424(322)/503 and heart disease has not been studied yet. Methods and Results: In this study, we created transgenic mice (TG) with tetracycline-controlled cardiomyocyte-specific miR-424(322)/503 expression. The TG mice and control mice (8 weeks) were fed with doxycycline-containing chow for up to a month. During this period, the weight of the mice and cardiac function were monitored. The weight of TG mice dropped significantly while controls grew normally. Echocardiography analysis showed continuous deterioration of cardiac function starting from 2 weeks. Ejection fraction and fractional shortening (n=8) decreased to 46±1.9% and 22±1.09% at 2 weeks and 15±2.7% and 6±1.2% at 4 weeks, respectively. In addition, left ventricular internal diameter (LVID,d and LVID,s) increased from 3.64±0.098 and 2.5±0.085 to 4.2±0.2 and 3.9±0.18 respectively. Morphologically, we found the hearts of TG mice to be larger than WT mice. H and E staining revealed dilated ventricular chambers and thinning of ventricular walls in TG. Likewise, fibrosis was observed in TG hearts through Masson trichrome stain. In addition, both atrial natriuretic peptides and brain natriuretic peptides increased by >8 folds in TG hearts (n=5). The level of β-MHC was higher while α-MHC was lower in TG hearts vs control. These indicate that TG phenotype is consistent with DCM. Conclusion: Overall, this is the first study showing that upregulated miR-424(322)/503 in the heart is sufficient to lead to DCM. This study can potentially help establish miR-424(322)/503 as a novel therapeutic target to ameliorate heart failure progression.