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J. Biol. Chem., Vol. 281, Issue 9, 5811-5820, March 3, 2006

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Selective Loss of Fine Tuning of G_q/11 Signaling by RGS2 Protein Exacerbates Cardiomyocyte Hypertrophy^*

From the Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

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.

Received for publication, July 20, 2005 , and in revised form, December 14, 2005.

^* This work was supported by NHLBI, National Institutes of Health, Grants HL-52320 and HL-72174 (to U. M.) and by Scientist Development Grant 9930032N (to U. M.), Grantin-aid 0555817T (U. M.), and a postdoctoral fellowship (to J. H.) from the American Heart Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Rhode Island Hospital and Brown Medical School, Cardiovascular Division, Cardiovascular Research Center, Southwest Pavilion 2nd floor, 593 Eddy St., Providence, RI 02903. Tel.: 401-444-9854; Fax: 401-444-9203; E-mail: UMende{at}Lifespan.org.

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