MicroRNA-30d is a biomarker for heart failure and plays a functional role in cardiac remodeling

Plasma microRNA-30d (miR-30d) correlates with left ventricular (LV) remodeling and clinical outcomes in heart failure (HF) patients, and miR-30d is protective against cardiomyocyte apoptosis in cell culture models. In rodent models of ischemic HF, we show that genetic, lentivirus or agomiR-induced miR-30d up-regulation in the heart improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte apoptosis. Genetic or locked nucleic acid (LNA)-based miR-30d expression reduction exacerbates pathological LV remodeling, with increased dysfunction, fibrosis, and cardiomyocyte death. miR-30d targets cardiomyocyte mitogen-associate protein kinase (MAP4K4), ameliorating apoptosis. Moreover, miR-30d is secreted in extracellular vesicles (EVs) by cardiomyocytes, mediating paracrine signaling to cardiac fibroblasts to inhibit fibroblast proliferation and activation by directly targeting integrin α5. Co-expression studies using whole blood mRNA and plasma circulating miR-30d expression in a large human cohort (Framingham Heart Study) further suggest the importance of miR-30d signaling in altering expression of genes implicated in fibrosis and inflammation. Collectively, these results support the notion of miR-30d as a functional biomarker that protects against LV remodeling and may be targeted as a therapy in HF.