The calcium-transporting ATPase ATP2A2, also known as SERCA2a, is a critical 
ATPase responsible for Ca(2+) re-uptake during excitation-contraction coupling. 
Impaired Ca(2+) uptake resulting from decreased expression and reduced activity 
of SERCA2a is a hallmark of heart failure. Accordingly, restoration of SERCA2a 
expression by gene transfer has proved to be effective in improving cardiac 
function in heart-failure patients, as well as in animal models. The small 
ubiquitin-related modifier (SUMO) can be conjugated to lysine residues of target 
proteins, and is involved in many cellular processes. Here we show that SERCA2a 
is SUMOylated at lysines 480 and 585 and that this SUMOylation is essential for 
preserving SERCA2a ATPase activity and stability in mouse and human cells. The 
levels of SUMO1 and the SUMOylation of SERCA2a itself were greatly reduced in 
failing hearts. SUMO1 restitution by adeno-associated-virus-mediated gene 
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 Ca(2+) decay. Transgene-mediated SUMO1 
overexpression rescued cardiac dysfunction induced by pressure overload 
concomitantly with increased SERCA2a function. By contrast, downregulation of 
SUMO1 using small hairpin RNA (shRNA) accelerated pressure-overload-induced 
deterioration of cardiac function and was accompanied by decreased SERCA2a 
function. However, knockdown of SERCA2a resulted in severe contractile 
dysfunction both in vitro and in vivo, which was not rescued by overexpression 
of SUMO1. Taken together, our data show that SUMOylation is a critical 
post-translational modification that regulates SERCA2a function, and provide a 
platform for the design of novel therapeutic strategies for heart failure.