Ryanodine receptor type 2 is required for the development of pressure overload-induced cardiac hypertrophy

Abstract

Ryanodine receptor type 2 (RyR-2) mediates Ca 2+ release from sarcoplasmic reticulum and contributes to myocardial contractile function. However, the role of RyR-2 in the development of cardiac hypertrophy is not completely understood. Here, mice with or without reduction of RyR-2 gene (RyR-2 +/- and wild-type, respectively) were analyzed. At baseline, there was no difference in morphology of cardiomyocyte and heart and cardiac contractility between RyR-2 +/- and wild-type mice, although Ca 2+ release from sarcoplasmic reticulum was impaired in isolated RyR-2 +/- cardiomyocytes. During a 3-week period of pressure overload, which was induced by constriction of transverse aorta, isolated RyR-2 +/- cardiomyocytes displayed more reduction of Ca 2+ transient amplitude, rate of an increase in intracellular Ca 2+ concentration during systole, and percentile of fractional shortening, and hearts of RyR-2 +/- mice displayed less compensated hypertrophy, fibrosis, and contractility; more apoptosis with less autophagy of cardiomyocytes; and similar decrease of angiogenesis as compared with wild-type ones. Moreover, constriction of transverse aorta-induced increases in the activation of calcineurin, extracellular signal-regulated protein kinases, and protein kinase B/Akt but not that of Ca 2+/calmodulin-dependent protein kinase II, and its downstream targets in the heart of wild-type mice were abolished in the RyR-2 +/- one, suggesting that RyR-2 is a regulator of calcineurin, extracellular signal-regulated protein kinases, and Akt but not of calmodulin-dependent protein kinase II activation during pressure overload. Taken together, our data indicate that RyR-2 contributes to the development of cardiac hypertrophy and adaptation of cardiac function during pressure overload through regulation of the sarcoplasmic reticulum Ca 2+ release; activation of calcineurin, extracellular signal-regulated protein kinases, and Akt; and cardiomyocyte survival. © 2011 American Heart Association, Inc.