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The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a potent target for cardiovascular diseases

Nature Clinical Practice Cardiovascular Medicine volume 5, pages 554–565 (2008)Cite this article

Abstract

The cardiac isoform of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) is a calcium ion (Ca2+) pump powered by ATP hydrolysis. SERCA2a transfers Ca2+ from the cytosol of the cardiomyocyte to the lumen of the sarcoplasmic reticulum during muscle relaxation. As such, this transporter has a key role in cardiomyocyte Ca2+ regulation. In both experimental models and human heart failure, SERCA2a expression is significantly decreased, which leads to abnormal Ca2+ handling and a deficient contractile state. Following a long line of investigations in isolated cardiac myocytes and small and large animal models, a clinical trial is underway that is restoring SERCA2a expression in patients with heart failure by use of adeno-associated virus type 1. Beyond its role in contractile abnormalities in heart failure, SERCA2a overexpression has beneficial effects in a host of other cardiovascular diseases. Here we describe the mechanism of Ca2+ regulation by SERCA2a, examine the beneficial effects as well as the failures, risks and complexities associated with SERCA2a overexpression, and discuss the potential of SERCA2a as a target for the treatment of cardiovascular disease.

Key Points

  • The sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) is an important therapeutic target for gene therapy in various cardiovascular diseases

  • Gene transfer of SERCA2a improves contractility and myocardial energetics in the setting of heart failure

  • Overexpression of SERCA2a has antiproliferative and vasodilatory effects on the vasculature

  • Gene transfer of SERCA2a has antiarrhythmic effects in the setting of calcium overload but its effects on ventricular arrhythmias in other cardiovascular disease states remain to be fully examined

  • The overall beneficial profile of SERCA2a targeting has led to the initiation of the first gene therapy trial to investigate the overexpression of SERCA2a via an adeno-associated vector in patients with heart failure

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Figure 1: The overexpression of SERCA2a in diseased hearts has been shown to result in the recovery of contractility.
Figure 2: Excitation–contraction coupling in cardiomyocytes.
Figure 3: The regulation of SR function via the adrenergic pathway.
Figure 4: A comparison of energy utilization between a normal and a failing heart and its normalization with SERCA2a overexpression.

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Acknowledgements

The investigators would like to thank Fadi G Akar, Lahouaria Hadri, Susumu Sakata, Yoshiaki Takewa, Hung Q Ly and Yasuyoshi Suzuki for consultations in their special respective fields. This work was supported in part by grants from the National Institutes of Health: R01 HL078691, HL057263, HL071763, HL080498, & HL083156, and a Leducq Transatlantic Network (RJ Hajjar).

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  1. Y Kawase is an Assistant Professor of Medicine, and RJ Hajjar is Director of Cardiovascular Research Center and a Professor of Medicine, at the Mount Sinai School of Medicine, New York, NY, USA.,

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Correspondence to Roger J Hajjar.

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Y Kawase is a stockholder for Celladon.

RJ Hajjar is a stockholder for and a patent holder/applicant for both Celladon and Nanocor.

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Kawase, Y., Hajjar, R. The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a potent target for cardiovascular diseases. Nat Rev Cardiol 5, 554–565 (2008). https://doi.org/10.1038/ncpcardio1301

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