Wrestling with heart failure: SUMO-1 to the rescue.

A small ubiquitin-like protein was shown to be beneficial to the failing heart through enhancing sarcoplas-mic reticulum Ca 2+ ATPase 2a (SERCA2a) stability and activity in a large animal model of heart failure. Dysregulation of calcium cycling in cardiomyocytes has been recognized as a major molecular mechanism of heart failure. SERCA2a plays a pivotal role in regulating calcium homeostasis, and reduction of SERCA2a activity has been recognized as a hallmark of heart failure. Hajjar and his colleagues 1 reported that the activity of SERCA2a is regulated by conjugation of small ubiquitin-like modifier-1 (SUMO-1) to SERCA2a. They also demonstrated that SUMO-1 gene delivery can restore SERCA2a expression and activity in the failing heart in a mouse model. Based on these findings, they postulated that SUMO modification (SUMOylation) is a critical regulator of SERCA2a function, which led to the design of SUMO-1 gene therapy in a swine ischemia–reperfusion heart failure model. 2 The authors performed a temporary balloon occlusion of the proximal left anterior descending artery to create myocardial infarction. One month later, 31 survived pigs were randomized to receive via antegrade coronary infusion either saline or adeno-associated vector type 1 (AAV1) loaded with SUMO-1 (low and high dose), SERCA2a, or both. They showed that both SUMO-1 and SERCA2a levels were increased in the pigs that received AAV1.SUMO-1 with or without AAV1.SERCA2a 2 months later. However, the changes in left ventricular ejection fraction (EF) were not statistically significant in all treated groups. Statistically significant changes were demonstrated in the maximal rate of pressure rise [dP/dt(max)] in the groups that received high-dose SUMO-1, SERCA2a, or both. Furthermore, the treated groups have less left ventricular dilatation. The authors concluded that SUMO-1 gene either alone or in combination with SERCA2a is beneficial in a large animal model of heart failure and holds promise for the treatment of heart failure in humans. SERCA2a is a calcium-ion pump that takes up calcium from the cytosol into the sarcoplasmic reticulum. 3 The expression level and activity of SERCA2a were found to be diminished in the failing heart. 4 In contrast to the well-known SERCA2a, SUMO is relatively unknown to the cardiovascular research community. SUMO belongs to a family of ubiquitin-like proteins that covalently attached to a large number of cellular proteins. SUMOylation is a versatile post-translational protein modification system that regulates a protein's cellular localization, function, and stability. 5 There are 3 different SUMOs: SUMO-1, SUMO-2, and SUMO-3 …