MicroRNA-mediated Regulation of SUMO1 Expression in Heart

Abstract

Background: Cardiac sarcoplasmic reticulum calcium ATPase pump (SERCA2a) is a key regulator in cardiac cells and its function and expression are decreased in heart failure (HF). Our group has shown that SERCA2a gene transfer induces beneficial effects in HF models and in patients with severe HF. Recently, our group determined that SERCA2a is SUMOylated by small ubiquitin related modifier type 1 (SUMO1), ultimately impacting cardiac function. The expression of SUMO1 in the myocardium is significantly decreased in failing hearts and its knockdown results in severe HF. However, the mechanisms by which SUMO1 is regulated remain unknown.

Methods/Results: To identify potential miRNAs targeting SUMO1, we first generated 19 candidates by sequence based prediction. Among 19 candidates, miR-146a was upregulated concurrently with SUMO1 expression in murine models of HF and in human HF ventricular tissues. Using a luciferase reporter assay, we confirmed that miR-146a targets the SUMO1 3’-untranslated region. Overexpression of miR-146a suppressed the expression of SUMO1 in mRNA and adversely affected the calcium transient in cardiomyocytes. Conversely, transfection of ‘decoy’ genes which has tandem complementary sequences of miR-146a increased both mRNA and protein of SUMO1. Introduction of miR-146a ‘decoy’ increased sumoylation of SERCA2a in cardiomyocytes.

Conclusion: These findings provide new insight into the regulation of SUMO1 in cardiomyocytes. It implies modulation of miR-146a is a potential target in HF therapy.