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Novel mode of SERCA (dys)regulation

Commented by Wolfgang A. Linke

Basic Science - Cardiac Diseases - Heart Failure
ESC Working Groups
Signal Transduction, Mechano-Transduction
Basic Science - Cardiac Diseases - Cardiomyopathies

Role of SIRT1 in modulating acetylation of the sarco-endoplasmic reticulum Ca2+-ATPase in heart failure

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.


  1. Kho C, Lee A and Hajjar RJ. Altered sarcoplasmic reticulum calcium cycling--targets for heart failure therapy. Nat Rev Cardiol. 2012; 9: 717-33. doi: 1038/nrcardio.2012.145
  2. Zsebo K, Yaroshinsky A, Rudy JJ, et al. Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality. Circ. Res. 2014; 114: 101-8. doi: 10.1161/CIRCRESAHA.113.302421
  3. Jessup M, Greenberg B, Mancini D, et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. 2011; 124: 304-13. doi: 10.1161/CIRCULATIONAHA.111.022889
  4. Kho C, Lee A, Jeong D, et al. SUMO1-dependent modulation of SERCA2a in heart failure. Nature. 2011; 477: 601-5.
  5. Adachi T, Weisbrod RM, Pimentel DR, et al. S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide. Nat. Med. 2004; 10: 1200-7.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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