miR-146a Suppresses SUMO1 Expression and Induces Cardiac Dysfunction in Maladaptive Hypertrophy.

<div>Rationale: Abnormal SUMOylation has emerged as a characteristic of heart failure (HF) pathology. Previously,</div><div>we found reduced SUMO1 (small ubiquitin-like modifier 1) expression and SERCA2a (sarcoplasmic reticulum</div><div>Ca2+-ATPase) SUMOylation in human and animal HF models. SUMO1 gene delivery or small molecule activation</div><div>of SUMOylation restored SERCA2a SUMOylation and cardiac function in HF models. Despite the critical role of</div><div>SUMO1 in HF, the regulatory mechanisms underlying SUMO1 expression are largely unknown.</div><div>Objective: To examine miR-146a–mediated SUMO1 regulation and its consequent effects on cardiac morphology</div><div>and function.</div><div>Methods and Results: In this study, miR-146a was identified as a SUMO1-targeting microRNA in the heart. A strong</div><div>correlation was observed between miR-146a and SUMO1 expression in failing mouse and human hearts. miR-146a</div><div>was manipulated in cardiomyocytes through AAV9 (adeno-associated virus serotype 9)-mediated gene delivery,</div><div>and cardiac morphology and function were analyzed by echocardiography and hemodynamics. Overexpression of</div><div>miR-146a reduced SUMO1 expression, SERCA2a SUMOylation, and cardiac contractility in vitro and in vivo. The</div><div>effects of miR-146a inhibition on HF pathophysiology were examined by transducing a tough decoy of miR-146a</div><div>into mice subjected to transverse aortic constriction. miR-146a inhibition improved cardiac contractile function</div><div>and normalized SUMO1 expression. The regulatory mechanisms of miR-146a upregulation were elucidated by</div><div>examining the major miR-146a–producing cell types and transfer mechanisms. Notably, transdifferentiation of</div><div>fibroblasts triggered miR-146a overexpression and secretion through extracellular vesicles, and the extracellular</div><div>vesicle–associated miR-146a transfer was identified as the causative mechanism of miR-146a upregulation in failing</div><div>cardiomyocytes. Finally, extracellular vesicles isolated from failing hearts were shown to contain high levels of miR-</div><div>146a and exerted negative effects on the SUMO1/SERCA2a signaling axis and hence cardiomyocyte contractility.</div><div>Conclusions: Taken together, our results show that miR-146a is a novel regulator of the SUMOylation machinery</div><div>in the heart, which can be targeted for therapeutic intervention.</div>