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

Abstract

Alterations in cardiac G protein-mediated signaling, most prominently Gq/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 Gq/11 signaling (transgenic expression of activated Gαq* 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 Cβ 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 Gq/11-mediated ERK1/2, p38, or JNK activation. Taken together, this study demonstrates that endogenous RGS2 exerts functionally important inhibitory restraint on Gq/11-mediated phospholipase Cβ 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 Gq/11-mediated remodeling. Furthermore, this study shows the feasibility of effective RNA interference in cardiomyocytes using lipid-based small interfering RNA transfection. Alterations in cardiac G protein-mediated signaling, most prominently Gq/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 Gq/11 signaling (transgenic expression of activated Gαq* 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 Cβ 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 Gq/11-mediated ERK1/2, p38, or JNK activation. Taken together, this study demonstrates that endogenous RGS2 exerts functionally important inhibitory restraint on Gq/11-mediated phospholipase Cβ 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 Gq/11-mediated remodeling. Furthermore, this study shows the feasibility of effective RNA interference in cardiomyocytes using lipid-based small interfering RNA transfection. Myocardial hypertrophy accompanies many forms of heart disease and develops in response to hemodynamic stress (such as pressure or volume overload), loss of contractile proteins after cardiac injury, or mutations in sarcomeric proteins. Many different stimuli and signaling pathways have been implicated in hypertrophy development (1Frey N. Olson E.N. Annu. Rev. Physiol. 2003; 65: 45-79Crossref PubMed Scopus (1193) Google Scholar). Among them, signaling events that are mediated by heterotrimeric Gq/11 proteins are of central importance (2Dorn II, G.W. Hahn H.S. Ann. N. Y. Acad. Sci. 2004; 1015: 225-237Crossref PubMed Scopus (22) Google Scholar). Gq/11 proteins are members of a protein family that transduces signals from many different G protein-coupled receptors (GPCRs) 3The abbreviations used are: GPCR, G protein-coupled receptor; RNAi, RNA interference; ANF, atrial natriuretic factor; KO, knock-out; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RT, reverse transcription; shRNA, short hairpin RNA; DMEM, Dulbecco's modified Eagle's medium; NVM, neonatal ventricular myocyte(s); AVM, adult ventricular myocyte(s); PBS, phosphate-buffered saline; PE, phenylephrine; Tim, timolol; ET-1, endothelin-1; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; PLC, phospholipase C. to generate diverse effects on myocyte growth, contractility, and heart rate (3Offermanns S. Prog. Biophys. Mol. Biol. 2003; 83: 101-130Crossref PubMed Scopus (220) Google Scholar). G proteins are subject to direct regulation by RGS (Regulators of G protein Signaling) proteins, which shorten the duration of the cellular response to external signals and generally cause a reduction in hormone sensitivity (4Hollinger S. Hepler J.R. Pharmacol. Rev. 2002; 54: 527-559Crossref PubMed Scopus (606) Google Scholar). Whereas their primary mode of action is acceleration of signal termination by decreasing the lifetime of active, GTP-bound Gα subunits, some RGS can also block signal generation by antagonizing Gα-mediated effector activation (5Anger T. Zhang W. Mende U. J. Biol. Chem. 2004; 276: 3906-3915Abstract Full Text Full Text PDF Scopus (71) Google Scholar). Thus, RGS proteins are believed to play an important role in fine tuning GPCR-induced signal transduction. Several RGS proteins are expressed in the heart, but their exact roles in the normal and diseased heart are still poorly defined (6Riddle E.L. Schwartzman R.A. Bond M. Insel P.A. Circ. Res. 2005; 96: 401-411Crossref PubMed Scopus (107) Google Scholar). Most cardiac RGS proteins belong to the B/R4 family of “small” RGS proteins that primarily consist of the Gα-binding RGS homology domain and short extensions (7Ross E.M. Wilkie T.M. Annu. Rev. Biochem. 2000; 69: 795-827Crossref PubMed Scopus (937) Google Scholar). They are mostly nondiscriminatory toward members of the Gq/11 and Gi/o subfamilies in vitro but tend to display greater specificity in intact cells (8De Vries L. Zheng B. Fischer T. Elenko E. Farquhar M.G. Annu. Rev. Pharmacol. Toxicol. 2000; 40: 235-271Crossref PubMed Scopus (513) Google Scholar). Myocardial expression studies to date have been restricted to a few RGS proteins and hearts that were already hypertrophic and/or failing (9Mittmann C. Chung C.H. Hoppner G. Michalek C. Nose M. Schuler C. Schuh A. Eschenhagen T. Weil J. Pieske B. Hirt S. Wieland T. Cardiovasc. Res. 2002; 55: 778-786Crossref PubMed Scopus (91) Google Scholar, 10Owen V.J. Burton P.B. Mullen A.J. Birks E.J. Barton P. Yacoub M.H. Eur. Heart J. 2001; 22: 1015-1020Crossref PubMed Scopus (58) Google Scholar, 11Zhang S. Watson N. Zahner J. Rottman J.N. Blumer K.J. Muslin A.J. J. Mol. Cell. Cardiol. 1998; 30: 269-276Abstract Full Text PDF PubMed Scopus (60) Google Scholar). At that stage, a multitude of signaling changes occur, many of which are probably secondary to the remodeling process. The first goal of the present study was to test the hypothesis that changes in the ventricular amount of Gq/11-regulating RGS proteins may precede hypertrophic remodeling and could therefore potentially of pathophysiological in Gq/11-regulating RGS to Gq/11 signaling and could or Gq/11-mediated a decrease in RGS could Gq/11 signaling and have a on RGS proteins that have been in cardiac (9Mittmann C. Chung C.H. Hoppner G. Michalek C. Nose M. Schuler C. Schuh A. Eschenhagen T. Weil J. Pieske B. Hirt S. Wieland T. Cardiovasc. Res. 2002; 55: 778-786Crossref PubMed Scopus (91) Google Scholar, 11Zhang S. Watson N. Zahner J. Rottman J.N. Blumer K.J. Muslin A.J. J. Mol. Cell. Cardiol. 1998; 30: 269-276Abstract Full Text PDF PubMed Scopus (60) Google and T. Biophys. 2001; PubMed Scopus Google Scholar, T. E.J. 1998; PubMed Scopus Google RGS2, and been to in cardiac T. E.J. 1998; PubMed Scopus Google was also in this RGS expression was in different models with enhanced Gq/11 U. A. A. J. E.J. Acad. Sci. U. S. A. 1998; PubMed Scopus Google in which enhanced signaling is restricted to remodeling signaling in as and pressure overload hypertrophy in response to aortic on Gq/11 signaling is G. 1998; PubMed Scopus Google Scholar, N. A. Wilkie T.M. J. S. 2001; PubMed Scopus Google Scholar). in to we RGS expression with a on changes that and a selective reduction in RGS2 protein and expression in both models prior to hypertrophy In the of the study, we the hypothesis that endogenous RGS2 Gq/11-mediated signaling and hypertrophy in cardiac and or not selective RGS2 functional the of other RGS proteins with potentially In to achieve that we identified targeting sequences that for effective and selective RNA interference of endogenous RGS2 and for in cardiac myocytes. in as a to of endogenous proteins. a by which RNA and of expression the of 2004; PubMed Scopus Google Scholar, P.A. Rev. Mol. Biol. 2003; PubMed Scopus Google Scholar). In of generation and of with expression of Gαq* have been described U. A. A. J. E.J. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, U. A. M. E.J. Circ. Res. PubMed Scopus Google Scholar, U. C. A. C. E.J. Mol. Cardiol. 2000; Full Text PDF Scopus Google Scholar). overload was by aortic in for as described M. L. J. S. 2002; PubMed Scopus Google Scholar). were and by the and on RGS expression in response to pressure overload hypertrophy due to aortic was of and for on the ventricular RNA was from ventricular and to that were with for RGS2, and and and an that been labeled with by The RGS were and with no other were to by were to or RNA from ventricular or of and aortic was reverse and with for and was on were in cardiomyocytes was on RNA using the with the were and RNA from neonatal and adult ventricular were to using for and and to the was in and and to the of in the and of The was for and for and for for a of The to the which in a the were using of for were and the of the was for RGS2 and but not or expression were therefore by for RGS2 and of and for on the was for on RGS expression in response to aortic from were to and with the were the not cells and neonatal ventricular were in with for and for was on in with a of was using the with as a of protein were on and to and the were with to and in phosphate-buffered and with the and as as the of RGS2 from B. and P. of and with and with secondary proteins of were by using secondary of endogenous RGS proteins by is due to their To the protein amount and proteins from ventricular were by for on and as described of RGS2 endogenous ventricular RGS2 protein by enhanced a in the that a RGS2 by C. W. of not and was in of by P. of from RGS2 is that the the of forms or RGS2 was in the from with to signal expression of RGS2 protein could not not of the other RGS2 also protein in the the that the were still present in RGS2, with other proteins. of RGS2 and interference sequences were using a were as with of of a of and the to homology to other homology or The sequences were as of a short hairpin and by a and the were and a the and a RNA and a RNA hairpin sequences of or homology to were used as and negative sequences were by and In to the sequences were and pressure by and cells were in and and using the of the was first in and with or the The and or RNA was or and of were used for and a the or was to transfection and cell The cells were in a with The was to with no or after transfection. were from by Circ. Res. 2000; PubMed Scopus Google from cells on a E. P.A. Circ. Res. PubMed Scopus Google and in of a ventricular were from by using A.J. R.A. J. Physiol. PubMed Google and on in with A. B. P. J. Mol. Cardiol. Full Text PDF PubMed Scopus Google Scholar). and were with or after in the as cells in different NVM, the transfection was of DMEM, and The transfection was with and after transfection. AVM, the transfection was to the and was with after transfection. of RGS2 was labeled with for in the to the and by of RGS2 were as described and cellular uptake was by in cells and cardiomyocytes was as described J. M. Cardiovasc. Res. PubMed Scopus Google Scholar). In cells were in a and for with in for were with in for or They were in or the by with or secondary from and from for Cβ was as a for as described U. A. M. E.J. Circ. Res. PubMed Scopus Google Scholar). after and were labeled in with The was the of or were in by and by was for to protein not of transfection of for or was to the for the or were with and in Signaling) with for and for of protein were on and to were with ERK1/2, p38, and JNK Signaling) that their forms and or both and and with and with secondary proteins of were by of transfection of for or was to the the myocyte size was in using was in for by of cell protein with with Circ. Res. 2000; PubMed Scopus Google Scholar). the of the cells were with PBS, by of cellular protein with for proteins were with in for and by are as for or of as is of were by test or of by for of were of Endogenous RGS in with Gq/11 and we expression of the major cardiac RGS proteins in different models of Gq/11-mediated both prior to and hypertrophic remodeling. with Gαq* that Gαq* expression in cardiac U. A. A. J. E.J. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, U. A. M. E.J. Circ. Res. PubMed Scopus Google and a and hypertrophic and signaling of and U. C. A. C. E.J. Mol. Cardiol. 2000; Full Text PDF Scopus Google that from both the with in heart with a rate of disease but a different of disease in the present study, were that the from normal to and failure in from were of cardiac is increased but ventricular and or expression are not increased and the is still from types by in and of and have a increased ventricular and and by the in from were and of of the disease of but disease toward the U. C. A. C. E.J. Mol. Cardiol. 2000; Full Text PDF Scopus Google for were that were primarily still in their and that already The most change in the hearts was a reduction in RGS2 by that was already in the in and in RGS2 to the was and and were also but to a on the of RGS2, and expression in and of are also in and increased and in the first of and that or after In RGS2 a in the of cardiac RGS development and and were to by and were therefore by the expression of was different but was not in both not with findings T. E.J. 1998; PubMed Scopus Google was in ventricular from and not to in Gαq* not in RGS2 down-regulation in prior to and after the development of the cardiac and in ventricular that RGS2 down-regulation was by a reduction in RGS2 protein as as of the in endogenous RGS2 to down-regulation was also in from after aortic that an in with RGS2 expression after were by and of The other RGS proteins were not of of or increased by on changes in RGS expression in response to pressure a of was from the of and for on the In that study, aortic to a in heart with after marked of and for on the a marked decrease in RGS2 was that for to In was not in from point for and were the but their were or to RGS2 the functional of selective down-regulation of endogenous RGS2 we the RGS2 for potential sequences and a RNA and a RNA for in for of expression of endogenous RGS2 in most cell potential sequences were first for their in RGS2 in cells that were with RGS2 of and not the by were in the or of the other but with cells that been with negative and still RGS2 expression was increased in the of was not by the negative with a transfection in cells the used endogenous expression by and RGS2 was and by that RGS2 was expressed and to generate and functional RGS2 could also direct of for sequences and not the for the expression of was to Endogenous RGS2 in RGS2 was also in cardiomyocytes using lipid-based transfection. uptake of fluorescently labeled RGS2 in after transfection that was still after not RGS2 uptake was and in of cells In AVM, cellular uptake of was also but to due to greater not neonatal adult changes in cell or transfection. The of both RGS2 in endogenous RGS2 was by and RGS2 a knockdown of RGS2 to of in both and AVM, The effect of RGS2 was for RGS2 was for to not and expression were with in both and with RGS2 and not expression of in both negative and RGS2 for and have not in Taken together, that endogenous RGS2 expression could and suppressed by transfection in of to Endogenous RGS2 on Gq/11-mediated the for the and RGS uptake and marked RGS2 was for functional we the response of the direct for to of different in that been with RGS2 or negative for of endogenous RGS2 increased the effect of activation in both and was not The effects of RGS2 sequences and were and could not to changes in the expression of endogenous or or not of endogenous RGS2 also to enhanced Gq/11-mediated activation of using short stimulation of for and or for with or in increased of ERK1/2, p38, and increased activation of of the in response to GPCR-induced Gq/11 activation the of was in cells that been with RGS2 with negative in to were for expression of this was to not ERK1/2, p38, and expression were of endogenous RGS2 to negative was by in transfection in Taken together, findings in to Gq/11-mediated activation was not enhanced RGS2 of to Endogenous RGS2 on Gq/11-mediated the hypertrophic response that Gq/11 activation P. A. S. Circ. Res. PubMed Scopus Google in cells with knockdown of endogenous In and were used that to a in cell size and and radiolabeled protein in was no in RGS2 with both a enhanced in cell size and protein selective RGS2 an enhanced hypertrophic study that endogenous ventricular RGS2 expression is in different hypertrophy models with enhanced Gq/11 signaling (transgenic Gαq* expression and pressure RGS2 down-regulation was and prior to the of identified targeting sequences that are effective and selective in RGS2 expression in and and that endogenous RGS2 exerts functionally important inhibitory restraint on Gq/11-mediated (but not activation and that loss of cardiac fine tuning of signaling by RGS2 down-regulation could potentially play a pathophysiological role in the development of Gq/11-mediated and of RGS2 in with Gq/11 on the role of RGS protein expression changes in the of cardiac hypertrophy and failure are still RGS expression been in with failing hearts and with failure (9Mittmann C. Chung C.H. Hoppner G. Michalek C. Nose M. Schuler C. Schuh A. Eschenhagen T. Weil J. Pieske B. Hirt S. Wieland T. Cardiovasc. Res. 2002; 55: 778-786Crossref PubMed Scopus (91) Google Scholar, 10Owen V.J. Burton P.B. Mullen A.J. Birks E.J. Barton P. Yacoub M.H. Eur. Heart J. 2001; 22: 1015-1020Crossref PubMed Scopus (58) Google and models of pressure overload and heart failure S. Watson N. Zahner J. Rottman J.N. Blumer K.J. Muslin A.J. J. Mol. Cell. Cardiol. 1998; 30: 269-276Abstract Full Text PDF PubMed Scopus (60) Google Scholar, T. Y. G. G. R.A. J. Physiol. Google Scholar). The findings were not due to and/or and were to a few RGS proteins and and already and failing hearts. The present study identified changes in RGS2 expression that the development of hypertrophy and may therefore of pathophysiological importance for the events hypertrophy development. the major endogenous cardiac RGS proteins, RGS2 was in expression prior to the development of RGS2 down-regulation was both and protein and in cardiac myocytes. was in models expression and pressure overload), that is a in hearts with enhanced Gq/11 In changes in and expression were to not in the Endogenous RGS the of RGS proteins been with proteins and by and is their role in regulation of cardiac G protein signaling by RGS proteins been described (9Mittmann C. Chung C.H. Hoppner G. Michalek C. Nose M. Schuler C. Schuh A. Eschenhagen T. Weil J. Pieske B. Hirt S. Wieland T. Cardiovasc. Res. 2002; 55: 778-786Crossref PubMed Scopus (91) Google Scholar, P. Blumer K.J. Muslin A.J. PubMed Scopus Google but studies primarily on the Gq/11 signaling and neonatal of cardiac development. a of we that RGS2 is a and selective of Gq/11-mediated activation and hypertrophy in cardiac myocytes, the other major cardiac RGS proteins can both Gq/11 and Gi/o signaling J. Zhang W. Michalek C. Mende U. 2005; Scholar). Whereas studies the of RGS proteins to cardiac G protein signaling, not the of endogenous is of importance in of generally expression of RGS proteins and the of RGS proteins with Gα In this study, we used a to the of endogenous RGS proteins in which a to used S. J. J. S. 2001; PubMed Scopus Google or inhibitory RGS Y. J.R. J. Res. 2004; PubMed Scopus Google targeting the A. E. S. Mol. Biol. PubMed Google or M. T. 2004; PubMed Scopus Google Scholar). and of in cells in the of or transfection can in cardiomyocytes using we and have transfection for with in some cell which to this in myocytes. In this study, we cellular uptake in of and effective and selective RGS2 in both and in cell or The effect was but to of Our findings that transfection of neonatal and adult cardiomyocytes could a to targeting in a and for effective (such as of M. C. Mullen M.G. A. J. G. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar, Y. J. N. M. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google and of A. M. M. N. M. J. Mol. Cardiol. 2004; Full Text Full Text PDF PubMed Scopus Google The transfection that can with this is to U. 2003; PubMed Scopus Google Scholar). transfection A. M. M. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google this study the was to neonatal and few Endogenous RGS2 Gq/11-mediated and and hypertrophy in response to stimulation were increased of endogenous RGS2 in and AVM, that RGS2 exerts functionally important inhibitory restraint on Gq/11-mediated activation in cardiac of different In to the of of the signaling p38, and to enhanced in response to Gq/11 activation RGS2 ERK1/2, p38, and JNK have been implicated to have effects in cell (such as that and JNK may not hypertrophy in in Circ. Res. 2002; PubMed Scopus Google Scholar, J. Mol. Cardiol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Cardiovasc. 2004; PubMed Scopus Google Scholar). of signaling by a of Sci. 2000; PubMed Scopus Google which could in to the of regulation of Gq/11-mediated activation by endogenous Furthermore, is that or of the other cardiac RGS proteins play a in targeting different sequences in RGS2 and a of RGS2 in They functional effects J. J. M. B. G. 2003; PubMed Scopus Google of Gq/11-mediated activation was the of with a to Gq/11 signaling J. Zhang W. Michalek C. Mende U. 2005; Scholar). Our findings not potential by other proteins (such as or in Gq/11-mediated but for the first a functionally important negative effect of endogenous Endogenous RGS2 activation in response to different receptors and that RGS proteins may not to with Gα proteins but may by the J.R. Mol. Pharmacol. 2003; PubMed Scopus Google Scholar). of RGS2 to sequences been described direct S. C. W. P. Hepler J.R. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google or a protein W. W. E.M. P.B. P. S. Biol. 2005; PubMed Scopus Google but we and G. S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, Blumer K.J. Mol. Pharmacol. 2005; PubMed Scopus Google have regulation of Gq/11 signaling by RGS2 to is important to that cellular a and RGS protein have to of a of to endogenous RGS2 in cardiomyocytes and to Taken together, this study shows that endogenous RGS2 proteins play a central role in fine tuning Gq/11 signaling and that RGS2 down-regulation in hearts with enhanced Gq/11 signaling Gq/11-mediated activation. that RGS2 can Gq/11-mediated activation in the of (5Anger T. Zhang W. Mende U. J. Biol. Chem. 2004; 276: 3906-3915Abstract Full Text Full Text PDF Scopus (71) Google Scholar). In Gαq* RGS2 down-regulation therefore probably in with a in endogenous and U. A. M. E.J. Circ. Res. PubMed Scopus Google Scholar, U. C. A. C. E.J. Mol. Cardiol. 2000; Full Text PDF Scopus Google to Gq/11 In pressure the role of Gq/11 signaling was by a marked reduction or of the hypertrophic response of the G. 1998; PubMed Scopus Google or of Gq/11 N. A. Wilkie T.M. J. S. 2001; PubMed Scopus Google Scholar). is that RGS2 down-regulation to of Gq/11 signaling in this as is to the functional of RGS2 down-regulation in of RGS2 in to a due to Gq/11 signaling and in the M.H. N. A. Muslin A.J. Blumer K.J. J. 2003; PubMed Scopus Google Scholar, P. M. Blumer K.J. Y. 2003; PubMed Scopus Google Scholar). enhanced that could to a of the to also to pressure in this J. M. Blumer K.J. A. J. J. Physiol. Physiol. 2005; PubMed Scopus Google Scholar). To is the cardiac of of have been which no of hypertrophy and normal M.H. N. A. Muslin A.J. Blumer K.J. J. 2003; PubMed Scopus Google Scholar). is that the in pressure in is not to hypertrophic changes or that hypertrophic changes a point in Furthermore, or not of RGS2 may to changes in the expression of other RGS proteins not been in of the studies to The present study that endogenous RGS2 fine Gq/11 signaling and in response to activation but not the response to hypertrophic stimuli in RGS2 protein-mediated signaling pathways are of importance for the regulation of cell and regulators of G protein signaling, RGS proteins an to the protein of this important protein family and the of endogenous RGS proteins normal and pathophysiological probably in Our findings endogenous RGS2 as an important negative of Gq/11-mediated activation and hypertrophy in that and selective down-regulation of RGS2 play a role in Gq/11-mediated hypertrophy The of changes in RGS2 expression also play a role in other forms of cardiac hypertrophy as a of or sarcomeric the subject of the expression and/or of RGS2 could potentially a to of the central pathways in hypertrophy development. is that negative regulators of hypertrophy could an important for heart failure to negative that are central for cellular J. Cardiovasc. Res. 2004; PubMed Scopus Google Scholar). hypertrophy is generally believed to an response that ventricular stress and cardiac but to heart that hypertrophy may not a and that may a N. Olson E.N. 2004; PubMed Scopus Google Scholar). B. and P. of for RGS2 and RGS2 and L. and S. W. for with the of and for on the are to for