Heart Accelerated Development of Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction in an RyR2-R176Q Knockin Mouse Model

In response to chronic hypertension, the heart compensates by hypertrophic growth, which frequently progresses to heart failure. Although intracellular calcium (Ca ) has a central role in hypertrophic signaling pathways, the Ca source for activating these pathways remains elusive. We hypothesized that pathological sarcoplasmic reticulum Ca leak through defective cardiac intracellular Ca release channels/ryanodine receptors (RyR2) accelerates heart failure development by stimulating Ca -dependent hypertrophic signaling. Mice heterozygous for the gain-of-function mutation R176Q/ in RyR2 and wild-type mice were subjected to transverse aortic constriction. Cardiac function was significantly lower, and cardiac dimensions were larger at 8 weeks after transverse aortic constriction in R176Q/ compared with wild-type mice. R176Q/ mice displayed an enhanced hypertrophic response compared with wild-type mice as assessed by heart weight:body weight ratios and cardiomyocyte cross-sectional areas after transverse aortic constriction. Quantitative PCR revealed increased transcriptional activation of cardiac stress genes in R176Q/ mice after transverse aortic constriction. Moreover, pressure overload resulted in an increased sarcoplasmic reticulum Ca leak, associated with higher expression levels of the exon 4 splice form of regulator of calcineurin 1, and a decrease in nuclear factor of activated T-cells phosphorylation in R176Q/ mice compared with wild-type mice. Taken together, our results suggest that RyR2-dependent sarcoplasmic reticulum Ca leak activates the prohypertrophic calcineurin/ nuclear factor of activated T-cells pathway under conditions of pressure overload. (Hypertension. 2010;55:932-938.)