Gorski PA et al.
An important feature of heart failure (HF) is diminished sarcoplasmic reticulum (SR) Ca2+-uptake, due to reduced expression and activity of the SR Ca2+-ATPase 2a (SERCA2a) (1). Phase 1 and 2a human trials have also demonstrated SERCA2a as an effective therapeutic target for HF (2, 3). During HF, it is not only the expression of SERCA2a that becomes altered, but dysregulated post-translational modifications (PTMs) to the protein have also been found to contribute to compromised Ca2+ homeostasis in disease. For instance, these PTMs include SUMOylation and S-glutathiolation (4, 5). In a new paper, Gorski et al. report a novel regulatory mechanism whereby lysine acetylation of SERCA2a directly affects its function. They show that acetylation of SERCA2a (at lysine position 492) is mediated by acetyltransferase p300, which could be reversed by the activity of the deacetylase sirtuin-1 (SIRT1). Importantly, they find that acetylation of SERCA2a occurs particularly in the setting of HF and can contribute to the contractile dysfunction. However, this contractile dysfunction in HF could be reversed by inhibition of SERCA2a acetylation through activation of SIRT1. These findings are interesting since the beneficial effects of SERCA2a deacetylation on cardiac function via SIRT1 activation suggest that targeting SERCA’s PTMs may provide a novel therapeutic strategy for the treatment of HF.