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

Rationale: Abnormal SUMOylation has emerged as a characteristic of heart failure (HF) pathology. Previously,we found reduced SUMO1 (small ubiquitin-like modifier 1) expression and SERCA2a (sarcoplasmic reticulumCa2+-ATPase) SUMOylation in human and animal HF models. SUMO1 gene delivery or small molecule activationof SUMOylation restored SERCA2a SUMOylation and cardiac function in HF models. Despite the critical role ofSUMO1 in HF, the regulatory mechanisms underlying SUMO1 expression are largely unknown.Objective: To examine miR-146a–mediated SUMO1 regulation and its consequent effects on cardiac morphologyand function.Methods and Results: In this study, miR-146a was identified as a SUMO1-targeting microRNA in the heart. A strongcorrelation was observed between miR-146a and SUMO1 expression in failing mouse and human hearts. miR-146awas manipulated in cardiomyocytes through AAV9 (adeno-associated virus serotype 9)-mediated gene delivery,and cardiac morphology and function were analyzed by echocardiography and hemodynamics. Overexpression ofmiR-146a reduced SUMO1 expression, SERCA2a SUMOylation, and cardiac contractility in vitro and in vivo. Theeffects of miR-146a inhibition on HF pathophysiology were examined by transducing a tough decoy of miR-146ainto mice subjected to transverse aortic constriction. miR-146a inhibition improved cardiac contractile functionand normalized SUMO1 expression. The regulatory mechanisms of miR-146a upregulation were elucidated byexamining the major miR-146a–producing cell types and transfer mechanisms. Notably, transdifferentiation offibroblasts triggered miR-146a overexpression and secretion through extracellular vesicles, and the extracellularvesicle–associated miR-146a transfer was identified as the causative mechanism of miR-146a upregulation in failingcardiomyocytes. Finally, extracellular vesicles isolated from failing hearts were shown to contain high levels of miR-146a and exerted negative effects on the SUMO1/SERCA2a signaling axis and hence cardiomyocyte contractility.Conclusions: Taken together, our results show that miR-146a is a novel regulator of the SUMOylation machineryin the heart, which can be targeted for therapeutic intervention.