RGS4 Reduces Contractile Dysfunction and Hypertrophic Gene Induction in Gα qOverexpressing Mice

Rogers, Jason H.; Tsirka, Anna E.; Kovács, Attila; Blumer, Kendall J.; Dorn, Gerald W.; Muslin, Anthony J.

doi:10.1006/jmcc.2000.1307

Cited by 67 publications

(56 citation statements)

References 38 publications

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“…Overexpression of Gαq recapitulates many aspects of both experimental cardiac hypertrophy and failure and the analogous human syndromes (16,23). Previous genetic manipulations have targeted proximal players of the Gαq signaling pathway to improve cardiac function and attenuate hypertrophy (25,(36)(37)(38)(39). Furthermore, a recent study has revealed that targeting molecules in the cell survival and death pathway may be especially critical to delay or prevent the progression of hypertrophy to heart failure in the Gαq-overexpressing mice (40).…”

Section: Discussionmentioning

confidence: 99%

Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy

et al. 2003

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IntroductionIn the face of unremitting hemodynamic stress, "adaptive" cardiac hypertrophy inevitably progresses to ventricular dilation and clinical heart failure, which affects an estimated 5 million Americans and has a mortality rate of approximately 50% in 4 years (1). A nearly universal characteristic of hypertrophied and failing myocardium is depressed sarcoplasmic reticulum (SR) Ca 2+ cycling, caused by decreased expression of the cardiac SR Ca 2+ ATPase (SERCA2a), by a relative overabundance of the SERCA2a inhibitory protein phospholamban (PLN), or by both (2, 3). Recent experimental successes have generated enthusiasm for treating heart failure by restoring SR Ca 2+ cycling, either through adenoviral-mediated myocardial-targeted expression of SERCA2a itself (4) or through antisense suppression (5) or genetic ablation of PLN (6), to relieve SERCA2a from endogenous inhibition. The common result of each approach is enhanced SR Ca 2+ cycling, which has improved energetics, survival, and cardiac function at the cellular, organ, and intact animal levels. Furthermore, there is no compromise in exercise performance or longevity in the case of PLN ablation (7,8).To date, PLN ablation or inhibition has improved SR Ca 2+ cycling and/or contractile function in transgenic Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca 2+ cycling. Normalization of Ca 2+ cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Gαq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-C MUT ) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca 2+ transients and enhanced unloaded fractional shortening with no change in SR Ca 2+ pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Gαq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Gαq pathway or MyBP-C mutations.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

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Section: Discussionmentioning

confidence: 99%

Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy

et al. 2003

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“…Transthoracic echocardiography was performed in awake mice by use of an Acuson Sequoia 256 Echocardiography System equipped with a 15-MHz transducer (model 15L8) as described previously (Siemens Medical Solutions, Mountain View, California, USA) (24,27). The echocardiographer was blinded in all cases to the transgenic status of the mice.…”

Section: Methodsmentioning

confidence: 99%

The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis

Zhang¹,

Weinheimer²,

Courtois³

et al. 2003

J. Clin. Invest.

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“…36 Primary antibodies used included the following: rabbit polyclonal anti-Raf-1 and anti-FLAG antibodies (Santa Cruz Biotechnology), rabbit polyclonal anti-phospho-p38 MAPK, anti-total-p38 MAPK, anti-cleaved caspase-3, antiphospho-JNK, anti-total-JNK, and anti-ERK1/2 antibodies (Cell Signaling Incorporated). Filters were extensively washed and then were incubated with horseradish peroxidase-conjugated anti-rabbit secondary antibody (Amersham).…”

Section: Protein Analysismentioning

confidence: 99%

“…35,36 Ascending aortic blood velocity was determined by Doppler echocardiography. A 5-MHz hand-held Doppler ultrasound probe (Acuson) was used to obtain transcutaneous aortic blood velocity waveforms in unanesthetized mice.…”

Section: Transthoracic Echocardiographymentioning

confidence: 99%

Raf-1 Kinase Is Required for Cardiac Hypertrophy and Cardiomyocyte Survival in Response to Pressure Overload

et al. 2004

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Background-Cardiac hypertrophy is a common response to pressure overload and is associated with increased mortality.Mechanical stress in the heart results in the activation of the small GTPase ras and the Raf-1/MEK/ERK signaling cascade in addition to other signaling pathways. Methods and Results-In an attempt to determine the requirement for the serine/threonine kinase Raf-1 in the pathogenesis of cardiac hypertrophy, we generated transgenic mice with cardiac-specific expression of a dominant negative form of Raf-1 (DN-Raf). DN-Raf mice appeared normal at birth, were fertile, and had normal cardiac structure and function in the absence of provocative stimulation. In response to pressure overload, cardiac extracellular signal-regulated kinase (ERK) activation was inhibited, but c-Jun N-terminal kinase (JNK) activation and p38 mitogen-activated protein kinase (MAPK) activation were normal. DN-Raf mice were sensitized to pressure overload and the development of cardiomyocyte apoptosis, and Ͼ35% of animals died within 7 days of aortic banding. Surviving DN-Raf animals were markedly resistant to the development of cardiac hypertrophy and hypertrophic gene induction in response to transverse aortic constriction. Conclusions-These results establish that Raf-1 kinase activity is essential for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload.

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RGS4 Reduces Contractile Dysfunction and Hypertrophic Gene Induction in Gα qOverexpressing Mice

Cited by 67 publications

References 38 publications

Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy

Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy

The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis

Raf-1 Kinase Is Required for Cardiac Hypertrophy and Cardiomyocyte Survival in Response to Pressure Overload

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