Dilated Cardiomyopathy in Two Transgenic Mouse Lines Expressing Activated G Protein αq: Lack of Correlation Between Phospholipase C Activation and the Phenotype

Mende, Ulrike; Semsarian, C.; Martins, D.C.; Kagen, Alexander; Duffy, C.Elise; Schoen, Frederick J.; Neer, Eva J.

doi:10.1006/jmcc.2001.1411

Cited by 37 publications

(65 citation statements)

References 33 publications

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“…We previously demonstrated that RGS2 can effectively diminish G q/11 -mediated PLC␤ activation in the absence of GTPase activity (5). In G␣ q * transgenic hearts, RGS2 down-regulation therefore probably acts in concert with a previously reported up-regulation in endogenous G␣ q/11 and PLC␤ (19,20) to further enhance G q/11 signaling. In pressure overload, the crucial role of G q/11 signaling was demonstrated by a marked reduction or absence of the hypertrophic response upon heart-specific disruption of the receptor-G q/11 interface (15) or deletion of G q/11 ␣ subunits (16).…”

Section: Feasibility and Significance Of Rnai In Cardiac Myocytesmentioning

confidence: 80%

“…In Vivo Models of Hypertrophy-The generation and respective phenotypes of two independent transgenic mouse lines with heart-specific expression of constitutively active G␣ q * have been described elsewhere (14,19,20). Pressure overload was induced by ascending aortic constriction in 2.5-month-old FVB mice for 8 weeks as described (21).…”

Section: Methodsmentioning

confidence: 99%

“…Transgenic Mice with Heart-restricted G␣ q * Expression-We previously reported that G␣ q * expression in vivo constitutively elevates cardiac PLC␤ activity (14,19) and provided a detailed phenotypic characterization (ventricular weights and hypertrophic marker gene expression, echocardiography, and signaling changes) of two independent lines (␣ q *52 and ␣ q *44h (20)). We reported that mice from both lines develop the same end stage phenotype (cardiac dilation with premature death in heart failure) with a similar rate of disease progression (within 2-3 months) but a very different time of disease onset (ϳ9 months later in ␣ q *44h).…”

Section: Expression Of Endogenous Rgs Proteins In Hearts With Enhancementioning

confidence: 99%

“…Because of the late disease onset (at ϳ10 -12 months of age) but rapid disease progression toward the end-stage phenotype within 2-3 months (see Ref. 20 for details), 12-14-month-old ␣ q *44h mice were grouped into mice that were primarily still in their "predilated" stage (gray bars) and those that had already reached "end stage" (black bars).…”

Section: Expression Of Endogenous Rgs Proteins In Hearts With Enhancementioning

confidence: 99%

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Selective Loss of Fine Tuning of Gq/11 Signaling by RGS2 Protein Exacerbates Cardiomyocyte Hypertrophy

Zhang¹,

Anger²,

Su³

et al. 2006

Journal of Biological Chemistry

105

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Alterations in cardiac G protein-mediated signaling, most prominently G q/11 signaling, are centrally involved in hypertrophy and heart failure development. Several RGS proteins that can act as negative regulators of G protein signaling are expressed in the heart, but their functional roles are still poorly understood. RGS expression changes have been described in hypertrophic and failing hearts. In this study, we report a marked decrease in RGS2 (but not other major cardiac RGS proteins (RGS3-RGS5)) that occurs prior to hypertrophy development in different models with enhanced G q/11 signaling (transgenic expression of activated G␣ q * and pressure overload due to aortic constriction). To assess functional consequences of selective down-regulation of endogenous RGS2, we identified targeting sequences for effective RGS2 RNA interference and used lipid-based transfection to achieve uptake of fluorescently labeled RGS2 small interfering RNA in >90% of neonatal and adult ventricular myocytes. Endogenous RGS2 expression was dose-dependently suppressed (up to 90%) with no major change in RGS3-RGS5. RGS2 knockdown increased phenylephrine-and endothelin-1-induced phospholipase C␤ stimulation in both cell types and exacerbated the hypertrophic effect (increase in cell size and radiolabeled protein) in neonatal myocytes, with no major change in G q/11 -mediated ERK1/2, p38, or JNK activation. Taken together, this study demonstrates that endogenous RGS2 exerts functionally important inhibitory restraint on G q/11 -mediated phospholipase C␤ activation and hypertrophy in ventricular myocytes. Our findings point toward a potential pathophysiological role of loss of fine tuning due to selective RGS2 down-regulation in G q/11 -mediated remodeling. Furthermore, this study shows the feasibility of effective RNA interference in cardiomyocytes using lipid-based small interfering RNA transfection.

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Section: Feasibility and Significance Of Rnai In Cardiac Myocytesmentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Expression Of Endogenous Rgs Proteins In Hearts With Enhancementioning

confidence: 99%

Section: Expression Of Endogenous Rgs Proteins In Hearts With Enhancementioning

confidence: 99%

See 2 more Smart Citations

Selective Loss of Fine Tuning of Gq/11 Signaling by RGS2 Protein Exacerbates Cardiomyocyte Hypertrophy

Zhang¹,

Anger²,

Su³

et al. 2006

Journal of Biological Chemistry

105

View full text Add to dashboard Cite

show abstract

“…In particular, the splicing variant phospholipase C␤1 seems to be involved in the hypertrophic responses initiated by Gq-coupled ␣1-adrenergic receptors in cardiomyocytes (65). However, other reports have shown a lack of correlation between phospholipase C␤ activation and the cardiac hypertrophy phenotype induced in transgenic mouse lines expressing activated G␣ q , suggesting a role for additional pathways in this process (66). In line with this notion, our data suggest that the functional link between G␣ q and PKC is also necessary for the development of G␣ q -induced cardiac hypertrophy programs.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C (PKC)ζ-mediated Gαq Stimulation of ERK5 Protein Pathway in Cardiomyocytes and Cardiac Fibroblasts

García-Hoz

Sánchez-Fernández

García‐Escudero

et al. 2012

Journal of Biological Chemistry

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Background: We have recently described that G␣ q acts as an adaptor protein that facilitates PKC-mediated activation of ERK5. Results: Our results show that PKC is essential for Gq-dependent ERK5 activation in cardiomyocytes and cardiac fibroblasts. Conclusion: This novel signaling axis plays a key role in cardiac hypertrophy programs. Significance: The G␣ q /PKC/ERK5 pathway would be active in such pathological settings, providing new therapeutic targets.

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Cardiac‐Specific Disruption of Bin1 in Mice Enables a Model of Stress‐ and Age‐Associated Dilated Cardiomyopathy

Laury‐Kleintop

Mulgrew

Heletz

et al. 2015

J of Cellular Biochemistry

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This article is protected by copyright. All rights reserved 3 Abstract Non-compensated dilated cardiomyopathy (DCM) leading to death from heart failure is rising rapidly in developed countries due to aging demographics, and there is a need for informative preclinical models to guide the development of effective therapeutic strategies to prevent or delay disease onset. In this study, we describe a novel model of heart failure based on cardiac-specific deletion of the prototypical mammalian BAR adapter-encoding gene Bin1, a modifier of ageassociated disease. Bin1 deletion during embryonic development causes hypertrophic cardiomyopathy and neonatal lethality, but there is little information on how Bin1 affects cardiac function in adult animals. Here we report that cardiomyocyte-specific loss of Bin1 causes ageassociated dilated cardiomyopathy (DCM) beginning by 8-10 months of age. Echocardiographic analysis showed that Bin1 loss caused a 45% reduction in ejection fraction during aging. Younger animals rapidly developed DCM if cardiac pressure overload was created by transverse aortic constriction. Heterozygotes exhibited an intermediate phenotype indicating Bin1 is haploinsufficient to sustain normal heart function. Bin1 loss increased left ventricle (LV) volume and diameter during aging, but it did not alter LV volume or diameter in hearts from heterozygous mice nor did it affect LV mass. Bin1 loss increased interstitial fibrosis and mislocalization of the voltagedependent calcium channel Ca v 1.2, and the lipid raft scaffold protein caveolin-3, which normally complexes with Bin1 and Ca v 1.2 in cardiomyocyte membranes. Our findings show how cardiac deficiency in Bin1 function causes age-and stress-associated heart failure, and they establish a new preclinical model of this terminal cardiac disease. This article is

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Dilated Cardiomyopathy in Two Transgenic Mouse Lines Expressing Activated G Protein αq: Lack of Correlation Between Phospholipase C Activation and the Phenotype

Cited by 37 publications

References 33 publications

Selective Loss of Fine Tuning of Gq/11 Signaling by RGS2 Protein Exacerbates Cardiomyocyte Hypertrophy

Selective Loss of Fine Tuning of Gq/11 Signaling by RGS2 Protein Exacerbates Cardiomyocyte Hypertrophy

Protein Kinase C (PKC)ζ-mediated Gαq Stimulation of ERK5 Protein Pathway in Cardiomyocytes and Cardiac Fibroblasts

Cardiac‐Specific Disruption of Bin1 in Mice Enables a Model of Stress‐ and Age‐Associated Dilated Cardiomyopathy

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