SUMO-1 gene transfer improves cardiac function in a large-animal model of heart failure

Lisa Tilemann, Ahyoung Lee, Kiyotake Ishikawa, Jaume Aguero, Kleopatra Rapti, Carlos Santos-Gallego, Erik Kohlbrenner, Kenneth M. Fish, Changwon Kho, Roger J. Hajjar

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93 Scopus citations

Abstract

Recently, the impact of small ubiquitin-relatedmodifier 1 (SUMO-1) on the regulation and preservation of sarcoplasmic reticulumcalcium adenosine triphosphatase (SERCA2a) function was discovered. The amount of myocardial SUMO-1 is decreased in failing hearts, and its knockdown results in severe heart failure (HF) inmice. In a previous study,we showed that SUMO-1 gene transfer substantially improved cardiac function in a murine model of pressure overload-induced HF. Toward clinical translation, we evaluated in this study the effects of SUMO-1 gene transfer in a swine model of ischemic HF.Onemonth after balloon occlusion of the proximal left anterior descending artery followed by reperfusion, the animalswere randomized to receive eitherSUMO-1 at two doses, SERCA2a, or both by adeno-associated vector type 1 (AAV1) gene transfer via antegrade coronary infusion. Control animals received saline infusions. After gene delivery, there was a significant increase in the maximum rate of pressure rise [dP/dt(max)] that was most pronounced in the group that received both SUMO-1 and SERCA2a. The left ventricular ejection fraction (LVEF) improved after high-dose SUMO-1 with or without SERCA2a gene delivery, whereas there was a decline in LVEF in the animals receiving saline. Furthermore, the dilatation of LV volumes was prevented in the treatment groups. SUMO-1 gene transfer therefore improved cardiac function and stabilized LV volumes in a large-animal model of HF. These results support the critical role of SUMO-1 in SERCA2a function and underline the therapeutic potential of SUMO-1 for HF patients.

Original languageEnglish
Article number211ra159
JournalScience Translational Medicine
Volume5
Issue number211
DOIs
StatePublished - 13 Nov 2013

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