SERCA2a stimulation by istaroxime: a novel mechanism of action with translational implications

Sarcoplasmic reticular (SR) Ca²⁺‐ATPase (SERCA2a) is central to cardiac electrophysiological and mechanical function. It ensures full diastolic relaxation minimizing delayed after‐potentials that would otherwise compromise membrane electrophysiological stability, and optimizes SR Ca²⁺ refilling and systolic contraction. Previous studies demonstrated that the small molecule agent istaroxime stimulates SERCA2a‐ATPase activity, restoring its function in failing hearts, and enhancing indices of mechanical, and SR Ca²⁺ release and re‐uptake, activity. Ferrandi et al (2013) now elegantly demonstrate its ability to dissociate the phospholamdan (PB) bound to cardiac SERCA2a, thereby removing the inhibitory effect of PB on SERCA2a. This effect was independent of the cAMP/PKA system and modified a specific SERCA2a reaction step. They used SERCA‐enriched SR preparations from a rigorously validated and realistic physiological, canine model of cardiac failure with established Na⁺‐K⁺‐ATPase sensitivity to cardiac glycosides and SR Ca²⁺ handling features. These findings potentially translate into a novel management of the major and increasingly important public health challenge of chronic cardiac failure.

Linked Article

This article is a commentary on Ferrandi et al., pp. 1849–1861 of volume 169 issue 8. To view this paper visit http://dx.doi.org/10.1111/bph.12278.

DOI: 10.1111/bph.12288

View this article

• Full article (html)
• Enhanced article (html)
• PDF
• References