Abstract 113: SUMO1 Gene Transfer Rescues Cardiac Function in a Large Animal Model of Heart Failure
Recently, small ubiquitin-related modifier 1 (SUMO1) was found to enhance the activity and stability of the cardiac sarcoplasmic reticulum Ca2+ ATPase, SERCA2a. In both, human and rodent models of heart failure (HF), the total amount of myocardial SUMO1 is decreased and its knock down results in severe HF. Adeno-associated vector (AAV) mediated SUMO1 gene transfer significantly improves cardiac function in murine models of HF. As a critical step towards clinical translation, we evaluated the effects of SUMO1 gene transfer in a swine model of ischemic heart failure. One month after balloon occlusion of the proximal LAD, 21 animals were randomized to receive either AAV1.SUMO1 at two doses, AAV1.SERCA2a, AAV1.SUMO1+AAV1.SERCA2a, or saline via antegrade coronary infusion. In addition, three pigs served as controls and underwent sham procedures. The ejection fraction and the maximum dP/dt significantly increased after gene transfer of SUMO1 at both doses, SERCA2a and the combination of SUMO1 and SERCA2a (p=0.034, p=0.028) compared to saline infusion. The increase in maximum dP/dt was most pronounced in the group that received both SUMO1 and SERCA2a. Furthermore, the increase in end-systolic and end-diastolic volumes was normalized in the treatment groups, while they further deteriorated in the saline group (p=0.001, p=0.022). SUMO1 and SERCA2a gene transfer significantly improved cardiac function and concomitant gene delivery of SUMO1 and SERCA2a had a synergistic effect on improving these parameters in the HF animals. These results strongly support the critical role of SUMO1 for SERCA2a function and underline the therapeutic potential in heart failure patients.
- © 2012 by American Heart Association, Inc.