RCAN1-Calcineurin Axis and the Set-Point for Myocardial Damage During Ischemia-Reperfusion.

Abstract

RCAN1 (regulator of calcineurin 1) is an endogenous inhibitor of the Ca2+-activated protein phosphatase calcineurin. It has been known for some time that deletion of RCAN1 in the mouse exacerbates ischemia/reperfusion-induced infarction in heart1 and brain.2 In this issue of Circulation Research , Parra et al3 elucidate an underlying mechanism. Article, see p e20 Calcineurin is a widely expressed serine/threonine phosphatase consisting of 1 catalytic and 1 regulatory subunit.4 This enzyme is activated by binding of Ca2+ to EF-hand motifs in the regulatory subunit and by calmodulin binding to the catalytic subunit. Calcineurin exerts pleiotropic effects including T-lymphocyte activation, neurite outgrowth, heart valve formation, skeletal myocyte differentiation, and cardiac and skeletal muscle hypertrophy. These effects are attributable primarily to calcineurin-mediated dephosphorylation of transcription factors (eg, NFAT [nuclear factor of activated T cells]5,6) resulting in their nuclear translocation and activation of various gene expression programs. Calcineurin, however, also acts on other substrates including structural proteins, receptors, channels, and signaling molecules.7 RCAN1, encoded by a gene in the Down syndrome critical region 1 on human chromosome 21, is enriched in striated muscle and brain.4 RCAN1 inhibits calcineurin through direct binding to its catalytic subunit. As might be expected from the actions of calcineurin, cardiomyocyte-specific overexpression of RCAN1 in mice inhibits cardiac hypertrophy elicited by pathological or physiological stimuli.8 Less expected are effects of RCAN1 on ischemia/reperfusion injury. Cardiomyocyte-specific transgenic overexpression ameliorates myocardial damage in vivo, whereas the opposite is observed in mice with generalized RCAN1 knockout.1 Moreover, pharmacological inhibition of calcineurin reverses this RCAN1-deficient phenotype showing that these effects of RCAN1 depletion are mediated by unleashing of calcineurin. So, what mechanisms connect RCAN1–calcineurin signaling with myocardial ischemia/reperfusion injury (Figure …