RGS4 Inhibits G-Protein Signaling in Cardiomyocytes

Tamirisa, Praveen; Blumer, Kendall J.; Muslin, Anthony J.

doi:10.1161/01.cir.99.3.441

Cited by 82 publications

(61 citation statements)

References 32 publications

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“…Negative regulation of cardiac G protein signaling by RGS proteins has been described (9,30), but these studies focused primarily on RGS4, the G q/11 signaling pathway, and neonatal stages of cardiac development. Using a similar type of overexpression studies, we recently demonstrated that RGS2 is a potent and selective inhibitor of G q/11 -mediated PLC␤ activation and hypertrophy in cardiac myocytes, whereas the other major cardiac RGS proteins (RGS3-RGS5) can regulate both G q/11 and G i/o signaling (31).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…We demonstrated recently that overexpression of RGS4 can inhibit the action of phenylephrine and endothelin-1, but not basic fibroblast growth factor, in cultured cardiomyocytes (32). To determine whether RGS4 could inhibit cardiac hypertrophy in an animal model system, we generated transgenic mice with a construct that contained the α-MHC promoter that has been demonstrated previously to direct modest embryonic and increased postnatal ventricular gene transcription (33).…”

Section: Generation Of Rgs4-myc Transgenic Micementioning

confidence: 99%

“…We have hypothesized that alterations in RGS gene expression may affect G protein-mediated signal transduction in the heart. To address this possibility, we found previously that overexpression of RGS4 in cultured cardiomyocytes inhibits phenylephrine-and endothelin-induced cardiomyocyte hypertrophy (32). To evaluate whether RGS4 overexpression could inhibit cardiac hypertrophy in response to physiological stimuli in live animals, we have generated a transgenic mouse model system.…”

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confidence: 99%

RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload

et al. 1999

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“…Human heart failure is associated with increased RGS4 expression, whereas expression of RGS2 is unchanged (7). Forced overexpression of RGS4 blunts G q -stimulated cardiac hypertrophy in rat neonatal cardiac myocytes (8) and intact hearts (9) and suppresses cardiac hypertrophy of transgenic mice lacking guanylate cyclase-A (natriuretic peptide-stimulated cyclase; ref. 10).…”

Section: Introductionmentioning

confidence: 99%

Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice

Takimoto¹,

Koitabashi²,

Hsu³

et al. 2009

J. Clin. Invest.

140

174

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The heart initially compensates for hypertension-mediated pressure overload by enhancing its contractile force and developing hypertrophy without dilation. G q protein-coupled receptor pathways become activated and can depress function, leading to cardiac failure. Initial adaptation mechanisms to reduce cardiac damage during such stimulation remain largely unknown. Here we have shown that this initial adaptation requires regulator of G protein signaling 2 (RGS2). Mice lacking RGS2 had a normal basal cardiac phenotype, yet responded rapidly to pressure overload, with increased myocardial G q signaling, marked cardiac hypertrophy and failure, and early mortality. Swimming exercise, which is not accompanied by G q activation, induced a normal cardiac response, while Rgs2 deletion in G αq -overexpressing hearts exacerbated hypertrophy and dilation. In vascular smooth muscle, RGS2 is activated by cGMP-dependent protein kinase (PKG), suppressing G q -stimulated vascular contraction. In normal mice, but not Rgs2 -/-mice, PKG activation by the chronic inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppressed maladaptive cardiac hypertrophy, inhibiting G q -coupled stimuli. Importantly, PKG was similarly activated by PDE5 inhibition in myocardium from both genotypes, but PKG plasma membrane translocation was more transient in Rgs2 -/-myocytes than in controls and was unaffected by PDE5 inhibition. Thus, RGS2 is required for early myocardial compensation to pressure overload and mediates the initial antihypertrophic and cardioprotective effects of PDE5 inhibitors.

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RGS4 Inhibits G-Protein Signaling in Cardiomyocytes

Abstract: These results demonstrate that RGS protein can inhibit G-protein-mediated signaling in vivo and suggest that increased expression of RGS protein may be a counterregulatory mechanism to inhibit G protein signaling.

Cited by 82 publications

References 32 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

RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload

Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice

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