Key result
Mice with the RyR2-R176Q mutation subjected to transverse aortic constriction displayed significantly lower cardiac function and enhanced hypertrophic response at 8 weeks compared with wild-type mice.
Why the study?
Does the RyR2-R176Q mutation accelerate heart failure development in mice subjected to transverse aortic constriction?
Does the RyR2-R176Q mutation accelerate heart failure development in mice subjected to transverse aortic constriction?
The RyR2-R176Q mutation accelerates pressure overload-induced cardiac hypertrophy and dysfunction in mice by activating the calcineurin/NFAT pathway via increased sarcoplasmic reticulum Ca(2+) leak.
RyR2-R176Q may accelerate pressure-overload HF in mice; hypothesis-generating for human relevance and requires validation before clinical consideration.
In response to chronic hypertension, the heart compensates by hypertrophic growth, which frequently progresses to heart failure. Although intracellular calcium (Ca(2+)) 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(2+)-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.
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Oort et al. (2010) studied Pressure overload-induced cardiac hypertrophy and dysfunction. RyR2-R176Q mutation vs. Wild-type mice was evaluated on Cardiac function, cardiac dimensions, and hypertrophic response. Mice with the RyR2-R176Q mutation subjected to transverse aortic constriction displayed significantly lower cardiac function and enhanced hypertrophic response at 8 weeks compared with wild-type mice.
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