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 ²⁺ source for activating these pathways remains elusive. We hypothesized that pathologiCal sarcoplasmic reticulum Ca ²⁺ leak through defective Cardiac intracellular Ca ²⁺ 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 ²⁺ 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 ²⁺ leak activates the prohypertrophic Calcineurin/nuclear factor of activated T-cells pathway under conditions of pressure overload.