ArticleHypertension (Dallas, Tex. : 1979)2010
Accelerated development of pressure overload-induced cardiac hypertrophy and dysfunction in an RyR2-R176Q knockin mouse model.
Article in Hypertension (Dallas, Tex. : 1979), 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35 citing papers in PubMed, 63 citations in OpenAlex.
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- Heart Plasticity in Response to Pressure- and Volume-Overload: A Review of Findings in Compensated and Decompensated Phenotypes.Frontiers in physiology · 2020Review
- TGR5 activation induces cytoprotective changes in the heart and improves myocardial adaptability to physiologic, inotropic, and pressure-induced stress in mice.Cardiovascular therapeutics · 2018Article
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- Sirtuin 5 is required for mouse survival in response to cardiac pressure overload.The Journal of biological chemistry · 2017Article
- Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling.Scientific reports · 2017Article
- Novel junctophilin-2 mutation A405S is associated with basal septal hypertrophy and diastolic dysfunction.JACC. Basic to translational science · 2017Article
- Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated CaInternational journal of cardiology · 2016Article
- RyR2 QQ2958 Genotype and Risk of Malignant Ventricular Arrhythmias.Cardiology research and practice · 2016Article
- Review of novel therapeutic targets for improving heart failure treatment based on experimental and clinical studies.Therapeutics and clinical risk management · 2016Review
- R4496C RyR2 mutation impairs atrial and ventricular contractility.The Journal of general physiology · 2016Article
- The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart.Cell reports · 2015Article
- Targeting cardiomyocyte Ca2+ homeostasis in heart failure.Current pharmaceutical design · 2015Review
- Reduced junctional Na+/Ca2+-exchanger activity contributes to sarcoplasmic reticulum Ca2+ leak in junctophilin-2-deficient mice.American journal of physiology. Heart and circulatory physiology · 2014Article
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8 authors at 1 institution in 1 country.
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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.
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