Extracellular vesicular MicroRNA-27a* contributes to cardiac hypertrophy in chronic heart failure

Under stress, the heart undergoes extensive remodeling resulting in cardiac fibrosis and hypertrophy, ultimately contributing to chronic heart failure (CHF). Alterations in microRNA levels are associated with dysfunctional gene expression profiles involved in the pathogenesis of heart failure. We previously showed that myocardial infarction-induced microRNA-enriched extracellular vesicles (EVs) contribute to the reduction in antioxidant enzymes by targeting Nrf2 signaling in CHF. MicroRNA-27a (miRNA-27a) is the predominant microRNA contained in cardiac fibroblast-derived EVs contributing to oxidative stress along with hypertrophic gene expression in cardiomyocytes. In the present study, we observed that miRNA-27a passenger strand (miRNA-27a*) was markedly upregulated in the non-infarcted area of the left ventricle of rats with CHF and encapsulated into EVs and secreted into the circulation. Bioinformatic analysis revealed that PDZ and LIM domain 5 (PDLIM5) is one of the major targets of miRNA-27a*, playing a major role in cardiac structure and function, and potentially contributing to the progression of cardiac hypertrophy. Our in vivo data demonstrate that PDLIM5 is down-regulated in the progression of heart failure, accompanied with the upregulation of hypertrophic genes and consistent with alterations in miRNA-27a*. Moreover, exogenous administration of miRNA27a* mimics inhibit PDLIM5 translation in cardiomyocytes whereas a miRNA27a* inhibitor enhanced PDLIM5 expression. Importantly, we confirmed that infarcted hearts have higher abundance of miRNA-27a* in EVs compared to normal hearts and further demonstrated that cultured cardiac fibroblasts secrete miRNA27a*-enriched EVs into the extracellular space in response to Angiotensin II stimulation, which inhibited PDLIM5 translation, leading to cardiomyocyte hypertrophic gene expression. In vivo studies suggest that the administration of a miRNA-27a* inhibitor in CHF rats partially blocks endogenous miR-27a* expression, prevents hypertrophic gene expression and improves myocardial contractility. These findings suggest that cardiac fibroblast-secretion of miRNA27a*-enriched EVs may act as a paracrine signaling mediator of cardiac hypertrophy that has potential as a novel therapeutic target.