Impaired calcium reuptake resulting from decreased expression and activity of SERCA2a is a hallmark of HF. The cardiac sarcoplasmic reticulum Ca 2+-ATPase (SERCA2a) is a key pump responsible for intracellular calcium handling and contractility in cardiac cells. For this reason, there is a critical need for novel targets and treatment strategies. Of all the cardiovascular diseases, HF is the only diagnosis increasing in both incidence and prevalence 2. There are 26 million people who suffer from heart failure (HF) in the world (5.8 million patients in the United States) 1. This first-in-class small-molecule activator targeting SERCA2a SUMOylation may serve as a potential therapeutic strategy for treatment of heart failure. N106 treatment increases contractile properties of cultured rat cardiomyocytes and significantly improves ventricular function in mice with heart failure. We identify a pocket on SUMO E1 likely to be responsible for N106’s effect. This compound directly activates the SUMO-activating enzyme, E1 ligase, and triggers intrinsic SUMOylation of SERCA2a. Here, we identify and characterize a small molecule, N106, which increases SUMOylation of SERCA2a. We have previously described a role for the small ubiquitin-like modifier type 1 (SUMO-1) as a regulator of SERCA2a and have shown that gene transfer of SUMO-1 in rodents and large animal models of heart failure restores cardiac function. Decreased activity and expression of the cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a), a critical pump regulating calcium cycling in cardiomyocyte, are hallmarks of heart failure.
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