Weighing in on heart failure: the role of SERCA2a SUMOylation.

Heart failure is a complex clinical syndrome resulting from structural changes in the myocardium that affects the ability of the ventricle to fill with or eject blood.1 It affects at least 5 million patients in the United States and consumes over 6% of our health care budget.1 Nearly half a million new patients are diagnosed to have heart failure each year and the incidence of new cases are increasing each year due to aging of the population and conversion of acute cardiac problems into chronic disorders. Coronary artery disease is the cause of heart failure in about two thirds of patients with left ventricular dysfunction. Without the ability for complete renewal, loss of functional cardiac myocytes due to MI or other causes will eventually lead to deterioration of myocardial function, resulting in heart failure. Heart failure is characterized by the impaired efflux of cytosolic Ca from the cell due to a sustained defect in SR Ca reloading and release.2 A reduced expression and/or activity of the calcium-transporting ATPase ATP2A2, also known as SERCA2a, is responsible for Ca reuptake during excitation–contraction coupling.3 Over the last decade or more, defective Ca2 uptake resulting from decreased expression and reduced activity of SERCA2a is recognized as a hallmark of heart failure. A recent study by Dr Roger Haijar and colleagues described as the “Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease” or CUPID showed that adenoviral restoration of SERCA2a expression improved cardiac function in heartfailure patients.4 Also, their latest investigation revealed an important role for regulating the SERCA2a through SUMOylation.5 The association of the small ubiquitin-related modifier (SUMO) conjugation pathway, an important posttranslational modification process, is a relatively new area and knowledge about the importance of the SUMO pathway for the development and maintenance of a normal cardiovascular system is just beginning to emerge (Reviewed in Wang and Schwartz6). SUMO modification is accomplished by the reversible attachment of SUMO family members to the acceptor lysine residue(s) located in the target proteins, with the help of activating, conjugating, and ligating enzymes and by Sentrin/SUMO-specific proteases (SENP).7 The process of SUMOylation alters the functional activity of targets by regulating protein–protein interactions, nucleocytoplasmic translocalization, protein-DNA binding activity, and/or protein stability. Kho et al5 showed that SERCA2a was SUMOylated at lysine residues 480 and 585, which proved to be critical for maintenance of SERCA2a ATPase activity. Their study revealed increased stability of SUMOylated SERCA2a in mouse and human myocytes. Although decreased SERCA2a levels have been well-documented in heart failure, the study by Kho et al was the first to reveal SUMO1 and the SUMOylation of SERCA2a were greatly reduced in failing hearts. SUMO1 gene therapy with adeno-associated-virusmediated delivery maintained the protein abundance of SERCA2a and markedly improved cardiac function in mice with heart failure. This effect was comparable to SERCA2A gene delivery. Moreover, SUMO1 overexpression in isolated cardiomyocytes augmented contractility and accelerated Ca2 decay. Viral-mediated SUMO1 overexpression rescued cardiac dysfunction induced by pressure overload conThe opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association. Commentaries serve as a forum in which experts highlight and discuss articles (published elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine. Commentaries are edited by Aruni Bhatnagar and Ali J. Marian. From the Department of Biology and Biochemistry University of Houston (R.J.S.), Stem Cell Laboratory Texas Heart Institute (R.J.S.), and Department of Cardiology (E.T.H.Y.), The University of Texas MD Anderson Cancer Center, Houston, Texas. Correspondence to Robert J. Schwartz, Department of Biology and Biochemistry, University of Houston, Location 466 UH Science Center, Houston, TX 77204-5001. E-mail [email protected] (Circ Res. 2012;110:198-199.) © 2012 American Heart Association, Inc.