The Role of/SUMO-1 in Cardiac Oxidative Stress and Hypertrophy

Abstract

Background: Small ubiquitin-like modifier type 1 (SUMO-1) has been shown to have a critical role in the dysfunction of the cardiac isoform of the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) in the setting of heart failure. In cardiac hypertrophy the role of SUMO-1 has not been defined and our study’s goals were to examine the effects of modulating SUMO-1 on the hypertrophic response in vitro and in vivo and to examine whether oxidative stress (during cardiac hypertrophy) is abrogated by SUMO-1 gene transfer. Results: In mice undergoing trans-aortic constriction (TAC), SUMO-1 levels increased slightly during the compensated stage of hypertrophy and then dropped sharply following the transition to heart failure. In isolated cardiomyocytes, SUMO-1 gene transfer inhibited hypertrophic responses in the presence of phenylephrine. AAV9 (adeno-associated vector type 9) gene transfer of SUMO-1 prevented the heart from hypertrophying following TAC and prevented the development of left ventricular dysfunction. Furthermore, SUMO-1 gene transfer blocked the negative effects of H2O2 on SERCA2a activity in cardiac myocytes, while in vivo indices of oxidative stress were decreased by SUMO-1 in cardiac hypertrophy and heart failure. Conclusion: The results of this study indicate that post-translational modifications of SERCA2a caused by the toxic environment of the hypertrophied and failing myocardium can be prevented by the expression of SUMO-1.