Role of MicroRNA-424(322)/503 in Heart Disease

Background: Cardiovascular disease is the topmost cause of death globally. Dilated cardiomyopathy (DCM), the most common cardiovascular diseases, is characterized by chamber dilation and systolic dysfunction eventually leading to heart failure. MicroRNAs have been shown to play an integral role in regulating the progression of cardiomyopathy and as a result have become novel targets for therapy. Previously, we found that miR-424(322)/503 is highly enriched in embryonic heart during early cardiac development but its expression drops to very low level after birth. Interestingly, other studies have revealed its upregulation in failing human hearts. However, the relation between miR-424(322)/503 and heart failure is not yet known. Methods and results: To understand the role of miR-424(322)/503 in the adult heart, we generated a tetracycline-controlled cardiomyocyte-specific miR-424(322)/503 expressing transgenic mice (TG). miR-424(322)/503 was induced in TG and wildtype (WT) mice (8 weeks) using doxycycline containing chow continuously for a month. The cardiac function was monitored every week. The tissues were harvested at the endpoint of the study for downstream analysis. We observed that the heart function of TG started deteriorating from 2 weeks of miR-424(322)/503 induction. Cardiac failure markers (ANP and BNP) were upregulated. Histology revealed dilated chambers with thin ventricular wall, presence of fibrosis and disorganized myocytes in TG, a phenotype consistent with DCM. We also observed that miR-424(322)/503-induced DCM progressed slowly with intermittent dose and even slower with lower dose of doxycycline. To further study the causative role, we removed the miR-424(322)/503 induction after 14 days and let them recover. We found that miR-424(322)/503-induced heart failure could be reversed by interrupting miR-424(322)/503 induction. RNA sequencing was done next to determine the genome-wide transcriptional changes. We observed several mitochondria-related genes and pathways to be downregulated. We also found mitochondrial dysregulation to be the common pathway between miR-424(322)/503-induced heart failure and human heart failure. Conclusion: Overall, this is the first study to show that upregulated miR-424(322)/503 in the heart is sufficient to lead to DCM and miR-424(322)/503-induced heart failure is reversible. We hypothesized that miR-424(322)/503-triggered DCM by dysregulating mitochondria. Thus, this study supports miR-424(322)/503 as a novel potential therapeutic target for DCM and heart failure.