Related Experiment Video
Updated: Jun 16, 2026
Transverse Aortic Constriction in Mice
Published on: April 21, 2010
Accelerated development of pressure overload-induced cardiac hypertrophy and dysfunction in an RyR2-R176Q knockin
Ralph J van Oort1, Jonathan L Respress, Na Li
1Department of Molecular Physiology and Biophysics, Baylor College of Medicine, 1 Baylor Plaza, BCM 335, Houston, TX 77030, USA.
Insights
Pathological calcium leak from the sarcoplasmic reticulum via defective ryanodine receptors (RyR2) accelerates heart failure. This leak activates prohypertrophic signaling pathways, worsening cardiac function under pressure overload.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Heart Failure Pathophysiology
Background:
- Chronic hypertension induces cardiac hypertrophy, a precursor to heart failure.
- Intracellular calcium (Ca(2+)) is crucial for hypertrophic signaling, but its source remains unclear.
Purpose of the Study:
- To investigate if sarcoplasmic reticulum Ca(2+) leak through defective ryanodine receptors (RyR2) accelerates heart failure.
- To determine the role of RyR2-dependent Ca(2+) leak in activating hypertrophic signaling pathways.
Main Methods:
- Utilized mice with a gain-of-function RyR2 mutation (R176Q/+) and wild-type controls subjected to transverse aortic constriction.
- Assessed cardiac function, dimensions, hypertrophy markers (heart weight:body weight, cardiomyocyte size), and gene expression (stress genes, regulator of calcineurin 1).
- Measured sarcoplasmic reticulum Ca(2+) leak and nuclear factor of activated T-cells (NFAT) phosphorylation.
Main Results:
- R176Q/+ mice showed significantly impaired cardiac function and increased cardiac dimensions post-constriction.
- Enhanced cardiac hypertrophy and increased expression of cardiac stress genes were observed in R176Q/+ mice.
- Pressure overload led to increased sarcoplasmic reticulum Ca(2+) leak, elevated regulator of calcineurin 1 (RCAN1) exon 4 expression, and decreased NFAT phosphorylation in R176Q/+ mice.
Conclusions:
- RyR2-dependent sarcoplasmic reticulum Ca(2+) leak contributes to accelerated heart failure development.
- This leak activates the prohypertrophic calcineurin/NFAT signaling pathway during pressure overload.
- Defective RyR2 function represents a potential therapeutic target for heart failure.
Abstract:
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.
