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 reticulum
Ca2+-ATPase) SUMOylation in human and animal HF models. SUMO1 gene delivery or small molecule activation
of SUMOylation restored SERCA2a SUMOylation and cardiac function in HF models. Despite the critical role of
SUMO1 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 morphology
and function.
Methods and Results: In this study, miR-146a was identified as a SUMO1-targeting microRNA in the heart. A strong
correlation was observed between miR-146a and SUMO1 expression in failing mouse and human hearts. miR-146a
was 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 of
miR-146a reduced SUMO1 expression, SERCA2a SUMOylation, and cardiac contractility in vitro and in vivo. The
effects of miR-146a inhibition on HF pathophysiology were examined by transducing a tough decoy of miR-146a
into mice subjected to transverse aortic constriction. miR-146a inhibition improved cardiac contractile function
and normalized SUMO1 expression. The regulatory mechanisms of miR-146a upregulation were elucidated by
examining the major miR-146a–producing cell types and transfer mechanisms. Notably, transdifferentiation of
fibroblasts triggered miR-146a overexpression and secretion through extracellular vesicles, and the extracellular
vesicle–associated miR-146a transfer was identified as the causative mechanism of miR-146a upregulation in failing
cardiomyocytes. 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 machinery
in the heart, which can be targeted for therapeutic intervention.