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

Ralph J. van Oort, Jonathan L. Respress, Na Li, Corey Reynolds, Angela C. De Almeida, Darlene G. Skapura, Leon J. De Windt, Xander H. T. Wehrens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


In response to chronic hypertension, the heart compensates by hypertrophic growth, which frequently progresses to heart failure. Although intracellular calcium (Ca2+) has a central role in hypertrophic signaling pathways, the Ca2+ source for activating these pathways remains elusive. We hypothesized that pathological sarcoplasmic reticulum Ca2+ leak through defective cardiac intracellular Ca2+ release channels/ryanodine receptors (RyR2) accelerates heart failure development by stimulating Ca2+-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 Ca2+ 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 Ca2+ leak activates the prohypertrophic calcineurin/nuclear factor of activated T-cells pathway under conditions of pressure overload. (Hypertension. 2010;55:932-938.)
Original languageEnglish
Pages (from-to)932-U216
Issue number4
Publication statusPublished - Apr 2010


  • calcium
  • heart failure
  • hypertrophy
  • ryanodine receptor calcium release channel
  • sarcoplasmic reticulum

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