SUMO-1 gene transfer improves cardiac function in a large-animal model of heart failure.
Recently, the impact of small ubiquitin-related modifier 1 (SUMO-1) on the regulation and preservation of sarcoplasmic reticulum calcium 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) in mice. 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. One month after balloon occlusion of the proximal left anterior descending artery followed by reperfusion, the animals were randomized to receive either SUMO-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.
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
Lisa
L
Tilemann
Ahyoung
A
Lee
Kiyotake
K
Ishikawa
Jaume
J
Aguero
Kleopatra
K
Rapti
Carlos
C
Santos-Gallego
Erik
E
Kohlbrenner
Kenneth M
KM
Fish
Changwon
C
Kho
Roger J
RJ
Hajjar
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology*; D025842:SUMO-1 Protein / Q000235:genetics*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics; D013552:Swine
D025842:SUMO-1 Protein; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases