[Frontiers in Bioscience S2, 547-557, January 1, 2010]
Deregulation of RGS2 in cardiovascular diseases
Sharon Tsang1, Anthony Yiu-Ho Woo1, Weizhong Zhu1, Rui-Ping Xiao1
1
TABLE OF CONTENTS
1. ABSTRACT
Alteration of G protein-coupled receptor (GPCR) signaling is a salient feature of hypertension and the associated heart diseases. Recent studies have revealed a large family of Regulators of G-protein Signaling (RGS) proteins as important endogenous regulators of GPCR signaling. RGS2 selective regulates Galphaq/11 signaling, an essential cause of hypertension and cardiac hypertrophy. Both clinical and animal studies have shown that deregulation of RGS2 leads to exacerbated Galphaq/11 signaling. There is an inverse correlation between RGS2 expression and blood pressure, as well as a selective down-regulation of RGS2 in various models of cardiac hypertrophy. The causal relationship has been established in animal studies. RGS2 knockout mice exhibit not only hypertension phenotype but also accelerated cardiac hypertrophy and heart failure in response to pressure-overload. Further in vitro studies have shown that RGS2 knockdown with RNA interference exacerbates, whilst RGS2 over-expression completely abolishes the Galphaq/11-induced hypertrophy. These findings indicate that deregulation of RGS2 plays a crucial role in the pathogenesis of cardiovascular diseases, marking RGS2 as a potential therapeutic target or biomarker of hypertension or hypertensive heart diseases.
2. INTRODUCTION
Hypertensive heart disease, characterized by hypertrophy of the left ventricles, is a major aetiological condition predisposing to heart failure (HF) , a leading cause of cardiac morbidity and mortality in developed countries. Catecholamines and vasoactive peptides such as angiotensin II and endothelin are chronically elevated in patients with hypertensive a heart disease, the increase of which perturbs the G-protein coupled receptor (GPCR) signal transduction and hastens the progression from cardiac hypertrophy to HF . Hypertension and cardiac hypertrophy are indeed characterized by exacerbated Galphaq/11 signaling, whereas HF is associated with up-regulated Galphai/o and depressed beta-adrenergic receptor (beta-AR) signaling .
Upon GPCR activation, guanosine diphosphate (GDP) is exchanged for guanosine triphosphate (GTP) on the Galpha subunit, resulting in the dissociation of the Gbeta-gamma subunit from the Galpha subunit. Both subunits activate downstream effectors. The intrinsic GTPase activity of the Galpha-subunit catalyzes the hydrolysis of GTP to GDP, thus reconstituting the heterotrimeric G-protein complex and terminating G-protein signaling . RGS proteins act as GTPase-activating proteins (GAPs) to accelerate this process, turning down GPCR signaling via returning G proteins to the GDP-bond heterotrimeric form. In addition to their GAP activity, RGS proteins also bind to certain effecter proteins such as adenylyl cyclase (AC) and the alpha-subunit of GalphaS proteins, resulting in inhibition of their functions .
GPCRs have been marked as targets for therapies. Among the most effective clinical treatments are angiotensin converting enzyme (ACE) inhibitors, beta-AR blockers, diuretics, and Ca2+ channel blockers , the administration of which reduces hypertension, concomitantly favors the regression of cardiac hypertrophy and fibrosis ; improves the symptoms of heart failure and reduces the 5-year mortality rates .
Despite the advances in medication targeting against altered GPCR signaling, cardiovascular diseases remain the leading cause of mortality . Thus, identification of novel therapeutic targets for cardiovascular diseases, particularly hypertensive heart diseases, is the current focus of cardiovascular research and medicine. In this regard, recent studies have revealed a large family of endogenous Regulators of G-protein Signaling (RGS) proteins which may be developed as potential therapeutic targets.
The small RGS B/R4 subfamily members, RGS2-5, are the predominant RGS proteins expressed in the cardiovascular system . RGS3-5 equally regulates both Galphai/o and Galphaq/11 whereas cardiac myocyte RGS2 displays selectivity for Galphaq/11 at least in part via the three unique residues within the G-protein binding domain . Given the critical role of Galphaq/11 in maladaptive cardiac hypertrophy and remodelling in hypertensive heart disease, RGS2 is gaining increasing attention as an intrinsic suppressor. Both clinical and basic studies have demonstrated that deregulation of RGS2 contributes to the pathogenesis of cardiovascular diseases . Clinical studies have exhibited an inverse relationship between blood pressure and RGS2 expression levels: hypertensive patients display a reduction in RGS2 mRNA and protein levels compared with normal subjects , whereas patients with Bartter's/Gitelman's syndrome who are characterized by hypotension show increased RGS2 expression , highlighting a correlation between deregulation of RGS2 and the pathogenesis of hypertension as well as hypotension. The potential causal relationship between RGS2 deficiency and the development of hypertension and associated heart disease has been substantiated by recent animal studies. First, mice lacking RGS2 have obvious hypertensive phenotype . Second, RGS2 deficient mice not only develop hypertension but also exhibit much more severe hypertensive heart disease as manifested by cardiac hypertrophy and heart failure in response to moderate pressure-overload as compared to wild-type controls . Additionally, the expression of RGS2, but not RGS3-5, is selectively down-regulated in multiple hypertrophic animal models , implying a crucial role of RGS2 deregulation in the development of cardiac hypertrophy. Finally, in vitro studies have further established the causal relationship between the reduction of RGS2 and cardiomyocyte hypertrophy . These findings indicate that deregulation or malfunction of RGS2 is critically involved in the pathogenesis of cardiovascular diseases, and that RGS proteins in general and RGS2 in particular may serve as novel therapeutic targets or biomarkers of hypertension or hypertensive heart diseases. In this review, we first give an overview of recent advances on the role of Galphaq/11-selective RGS2 in cardiovascular diseases. We focus on hypertension and cardiac hypertrophy, which are accompanied with exacerbated Galphaq/11 signaling. Finally, we discuss the regulation of RGS2 and its potential pathogenic and therapeutic implications.
3. THE ROLE OF RGS2 AND cardiovascular disease
3.1 Deregulation of RGS2 in the vascular system and hypertension
Hypertension is a major risk factor for ischemic heart diseases and a strong predictor of hospitalization for congestive heart failure (CHF) . Accumulating evidence shows that RGS2 plays a prominent role in regulating GPCR signaling pathways that directly involved in blood pressure homeostasis. First, RGS2 expression has been detected in vascular smooth muscle, the dysfunction of which contributes to pathogenesis of hypertension . Second, RGS2 selectively regulates Galphaq/11 signaling, which is activated by many vasoconstrictors including vasopressin, endothelin-1 (ET-1), thromboxane A2 thrombin, and angiotensin II. These observations suggest that the deregulation of RGS2 may promote chronic constriction of the peripheral vasculature, leading to hypertension . More importantly, hypertensive patients indeed display a decrease in RGS2 mRNA and protein levels . Conversely, patients with Bartter's/Gitelman's syndrome, whom are accompanied with hypotension, have an enhanced expression of RGS2 (Table 1). Further studies of genetic variations in RGS2 in human hypertension populations have been reported . Polymorphisms in RGS2 significantly reduce its expression as well as its action in inhibiting angiotensin II receptor type I (AT1)-mediated accumulation of inositol phosphates, thereby hastening the pathogenesis of hypertension . That RGS2 is associated with blood pressure regulation is further supported by a recent study showing the association of G/G 1114 RGS2 genotype with the number of neutrally mediated syncope (NMS) episodes, which is also a type of blood pressure dysregulation .
The essential role of RGS2 in the regulation of vascular tone has been well demonstrated in mice lacking RGS2. Tang et al have shown that mice lacking RGS2 at the age of 3-5 months globally develop modest systemic hypertension and a striking elevation in mean arterial pressure without major cardiac phenotype at resting conditions . Furthermore, it has been shown that RGS2 knockout mice are hypertensive and exhibit persistent constriction of the resistance vasculature . Consistent with these findings, RGS2-/- mice have more severe hypertension and prolonged vasoconstriction in response to angiotensin II as compared to wild type control animals .
Interestingly, Heximer and co-workers have demonstrated that both anesthetized rgs2+/- and rgs2-/- mice display substantial blood pressure elevation, indicating that that both copies of the rgs2 gene are essential for normal regulation of blood pressure. Furthermore, they have also reported that the elevated blood pressure in RGS2-/- mice, unlike in many other hypertensive mouse models, is not accompanied by a compensatory fall in heart rate, suggesting that the absence of normal RGS2 function may also cause generalized disruption of cardiovascular reflexes. Taken together, both clinical and basic studies have demonstrated that RGS2 constitutes a requisite for the regulation of normal vascular tone and blood pressure, and that a reduction or malfunction of RGS2 contributes to the pathogenesis of hypertension.
3.1.1. Potential role of Galpha12/13
A previous study by Wirth et al have shown that both Galphaq/11 and Galpha12/13 are required for salt-induced hypertension despite only Galphaq/11 is necessary to maintain normal blood pressure . Given that vasoconstrictors such as angiotensinII, endothelin-1 or throboxaneA2 receptors couple to Galphaq/11 and Galpha12/13, RGS2 might as well regulates Galpha12/13. Further studies are needed to elucidate the effect of RGS2 on Galpha12/13.
3.2 Deregulation of RGS2 and cardiac hypertrophy
Hypertension is one of the conditions which increases afterload and is a precipitating cause of cardiac hypertrophy. The myocardium responds to acute overload by undergoing hypertrophy, which was originally described as a compensatory mechanism to reduce wall stress during acute overload . However, sustained stress initiates a myopathic transition from a compensatory state to progressive chamber enlargement associated with impaired myocardial vascularization, unfavourable changes in the extracellular matrix composition and fibrosis . It is well accepted that pathological hypertrophy is associated with adverse prognosis. Clinical consequences include the development of cardiac arrhythmias, cardiac dysfunction and eventually CHF .
3.2.1. Galphaq/11 signaling and cardiac hypertrophy
The contribution of G proteins to cardiac hypertrophy and heart failure has been extensively examined in transgenic mouse model systems . Despite the finding showing that cardiac hypertrophy can be mediated through vascular actions , substantial evidence shows that Galphaq/11 in the myocardium is the central player for pressure overload-induced cardiac hypertrophy (Figure 1). Cardiac specific over-expression of Galphaq/11 results in the development of cardiac hypertrophy and dilatation, subsequently leads to cardiomyopathy with depressed contractile function , the effect of which is blocked by cardiac specific expression of an inhibitor of Galphaq/11 signaling .
3.2.2. Role of RGS2 in cardiac hypertrophy
Among multiple RGS proteins, RGS2 is selectively down-regulated in hypertrophy animal models . The selective down-regulation of RGS2 occurs even before the onset of cardiac hypertrophy . Furthermore, Zhang et al have demonstrated that over-expression of RGS2 inhibits Galphaq/11-mediated cardiac myocyte hypertrophy, whereas gene silencing of RGS2 with RNAi exacerbates cardiac myocyte hypertrophy in response to increased Galphaq/11 signaling by the stimulation of ET-1 receptor with endothelin or alpha1-adrenoceptor (alpha1-AR) with phenylephrine (PE) . In support of this, it has been shown that RGS2 directly interacts with the third intracellular loop of alpha1A-adrenergic receptor . Importantly, studies on RGS2 deficient mice have further established a causal relationship between reduced RGS2 expression and cardiac hypertrophy. Specifically, RGS2-/- mice exhibit a very marked hypertrophic response, cardiac dysfunction and premature death in response to pressure overload . Although RGS2-/- and its littermates have similar resting cardiac anatomy and functions at the age of 4-5 months in the absence of pressure overload , RGS2 deficient mice display a marked dilation following pressure overload, which is accompanied with a significant increase in end-diastolic and systolic dimensions and decline in fractional shortening as well as impaired relaxation compared with littermate controls . These results suggest that dysfunction of RGS2 may play a prominent role in the initial events that trigger hypertrophy in response to pressure overload.
3.2.3. Potential mechanisms underlying RGS2-mediated suppression of hypertrophy
Apart from the converging point on Galphaq/11, the exact molecular mechanism underlying RGS2-mediated suppression of hypertrophy remains highly controversial. Zhang et al have shown that RGS2 restrains Galphaq/11 mediated hypertrophy via suppressing phospholipase C-beta (PLC-beta) but not MAPK activation . However, Takimoto et al have recently demonstrated that pressure overload-induced cardiac dilation and hypertrophy in RSG2-/- mice are coupled with exacerbated activation of ERK1/2 and JNK and a concurrent increase in calcineurin, regulator of calcineurin-1 (RCAN-1) and CAMKII activity (Figure 1), which have previously been implicated in maladaptive cardiac remodelling . Of note, the aforementioned effects are blocked by the administration of a PLC-beta inhibitor U73122 (Figure 1). Nevertheless, the exact mechanism underlying RGS2-mediated suppression of hypertrophy awaits further investigation.
3.2.4. Potential overlapping role of RGS proteins
Although compelling evidence indicates that reduced RGS2 expression is central in the development of hypertrophy in response to pressure overload and that RGS2 is 10 folds more potent than RGS4 in blocking Galphaq/11 activation of PLC-beta , recent studies have highlighted a complex and potential overlapping roles of RGS proteins. Over-expression of RGS4 has been shown to inhibit endothelin-1 or PE-induced cardiac myocyte hypertrophy and blunts Galphaq/11 stimulated cardiac hypertrophy in mice . Furthermore, Kangawa and co-workers have recently demonstrated that RGS4 is required for the cardiac natriuretic peptides mediated anti-hypertrophic effect in the heart . However, RGS4 over-expressing hearts exhibit rapid cardiac dilation and marked mortality in response to pressure overload . Further studies are warranted.
3.3 Role of RGS2 in the development of heart failure
Hypertension and pathophysiological hypertrophy are well-established risk factors of congestive heart failure (CHF) . Long-standing arterial hypertension induced cardiac hypertrophy is indeed associated with a marked increase in incidence of heart failure. Kass and co-workers have recently provided strong evidence that RGS2 ablation renders the heart more vulnerable and results in premature death despite the inconsistent expression profile of RGS2 in CHF . In response to pressure overload, RGS2-/- mice are acutely decompensated with dilated heart failure and associated with a significantly higher mortality compared with the littermate controls.
It is well documented that enhanced Galphai/o-mediated signaling , in addition to Galphaq/11-dependent signaling, plays a pivotal role in the progression to heart failure. A previous study has shown that RGS2 has no effect on Galphai/o-coupled signaling in adult rat cardiac myocytes . However, our unpublished biochemical and functional data have shown that RGS2 served as an endogenous negative regulator of beta2-adrenergic receptor (beta2-AR)-activated Galphai/o signaling in rodent cardiomyocytes (Zhu et al., personal communication). Adenovirus mediated RGS2 over-expression abrogated beta2-AR-Galphai/o coupling in cultured cardiac myocytes, which was intact in RGS2-/- mice. In support of this finding, RGS2 has been shown to directly interact with beta2-AR . Furthermore, RGS2 may directly inhibit the major myocardial adenylyl cyclase V and VI isoforms , the impaired activity of which is a feature of HF. It is likely that the selective down-regulation of RGS2 in hypertrophic hearts or early stage compensated failing hearts leads to increased Galphai/o as well as Galphaq/11 signaling, thus contributing to the transition of compensated to decompensated CHF.
The central importance of exacerbated Galphai/o signaling in HF further implies the potential involvement of RGS3-5. While RGS3 and RGS4 have been shown to be increased in myocardium from patients with HF , there is also reports argue against the notion . The disparity might be, at least in part, owing to the complex aetiology of HF and the dynamic regulation of a multitude of RGS proteins (see below). Taken together, previous studies have provided compelling evidence to support a prominent role of RGS2 deregulation in the development of cardiac hypertrophy, whilst it is possible that other RGS proteins may play a role.
4. Regulation of RGS2
4.1 G-protein dependent regulation of RGS2 expression
It has been shown that the regulation of RGS2 expression and activity is both tissue- and receptor-specific. In the cardiovascular system, the gene and protein expression of RGS2 is dynamically regulated by stimulation of a variety of GPCR-coupled signaling pathways (Table 2).
4.1.1. Galphaq/11-RGS2-Galphaq/11 negative feedback loop
Galphaq/11-selective RGS2 has been shown to undergo rapid up-regulation in the myocardium in response to Galphaq/11 activation (Figure 1). Acute increase in Galphaq/11 signaling evoked by receptor activation or enforced expression of a constitutively active Galphaq/11 mutant, Galphaq/11*, selectively up-regulate myocardial RGS2 but not RGS3-5 . In agreement with this finding, Hao et al have showed that the alpha1-AR agonist PE robustly increases RGS2 gene expression by 20 folds. Similarly, administration of phorbol-12-myristate-13-acetate (PMA), a PKC activator, also increases RGS2 by 110 folds over the baseline . Similar findings have been reported in vascular smooth muscle cells. Grant et al have demonstrated that angiotensin II-mediated activation of AT-1 selectively stimulates the gene expression of RGS2 in vascular smooth muscle cells in a dose- and time-dependent manner . It has been suggested that the rapid increase in RGS2 expression in response to the stimulation of a given Galphaq/11 coupled-GPCR might serve as a negative feedback loop to facilitate the termination of the receptor signaling.
4.1.2. GalphaS-RGS2-Galphaq/11/Galphai/o signaling cross-talk?
Interestingly, Hao et al demonstrated that stimulation of GalphaS-coupled beta-AR with isoproterenol (ISO) also increases RGS2 at both mRNA and protein levels (Figure 1). Similar findings have been obtained with administration of forskolin, which directly activates AC . These findings are in agreement with previous notion of cAMP-dependent regulation of RGS2 in other cell types . Consistent with these findings, our laboratory has recently shown that administration of ISO increases expression of RGS2 (unpublished results) in rodent cardiac myocytes. Since RGS2 has no GAP activity toward the alpha-subunit of Gs proteins , the up-regulation of RGS2 by activation of Gs-coupled signaling is unlikely to represent a negative feedback mechanism, instead highlighting a potential cross-talk between GalphaS and Galphaq/11- or Galphai/o-mediated signaling pathways in the cardiac myocytes (Figure 1).
4.1.3. Biphasic regulation of RGS2 expression
Evidence has accrued that RGS2 expression undergoes a biphasic regulation, with an initial rise followed by a persistent decline in response to sustained agonist stimulation. To date, most studies have shown that up-regulation of RGS expression is rapid. For instance, stimulation of AT-1 receptor with angiotensin II markedly increases mRNA and protein expression of RGS2 within 1h . Likewise, Hao et al have also demonstrated that PE-induced up-regulation of RGS2 occurs within the first hour of agonist treatment. Our unpublished data have also shown that administration of ISO for 2h increases RGS2 protein expression in adult mouse and rat cardiac myocytes (Zhu et al., personal communication).
Despite an acute increase following administration of GPCR agonists, RGS2 expression declines in response to sustained stimulation. For instance, Hao et al have shown a significant decrease in RGS2 expression at 72h after administration of PE or PMA . In support of the finding, our lab has also demonstrated a marked down-regulation of RGS2 protein after 24h ISO or forskolin stimulation in cultured mouse cardiomyocytes (Unpublished results).
4.1.4 Deregulation of G-protein-dependent axis and its pathophysiological implications
It has been suggested that the eventual decline of RGS2 induced by prolonged GPCR stimulation may serve as an important pathological element via loss of control of certain G-protein signaling, in particular, Galphaq/11 and Galphai/o signaling. In support of this perception, Zhang et al have provided eloquent evidence that there is a selective RGS2 down-regulation with prolonged enhanced Galphaq/11 signaling in the hypertrophic heart , suggesting that the down-regulation of RGS2 and the subsequent exacerbated Galphaq/11 signaling in response to chronic elevated catecholamines in diseases states may, at least in part, contribute to the pathogenesis of cardiovascular diseases including hypertension and myocardial hypertrophy.
4.2 PKG-dependent regulation of RGS2 activity
4.2.1. G-protein-independent regulation of RGS2 by NO-cGMP-PKG signaling cascade in VSMC
Eloquent evidence shows that RGS2 activity can be regulated through a GPCR/G-protein independent mechanism via activation of the NO-cGMP-PKG axis . PKGI-alpha, the predominant PKG isoform in vascular smooth muscle cells, has been shown to inhibit vascular contraction by phosphorylating RGS2 at Ser46 and 64, which modestly increases its GAP activity toward Galphaq/11 by 2-folds , thereby terminating Galphaq/11-mediated vasoconstriction .
The role of PKG in regulating RGS2 is further supported by the fact that mice lacking RGS2 have an impaired cGMP-mediated inhibition on Ca2+ transients elicited by vasoconstrictors , and display decreased cGMP-mediated relaxation . Furthermore, it has been shown that cGMP stimulation increases the translocation of wild type RGS2, but not its mutant which lacks PKG phosphorylation sites, to smooth muscle cell plasma membranes, a prerequisite for its activity. Similarly, Blumer and co-workers have demonstrated that PKG-dependent plasma membrane association of RGS2 is necessary for RGS2-mediated inhibition of vasoconstrictor- and Galphaq/11-triggered PLC activation, Ca2+ release, and capacitative Ca2+ entry .
4.2.2. G-protein-independent regulation of RGS2 by cGMP-PKG-PDE5 signaling axis in the heart
PKG-dependent regulation of RGS2 has also been demonstrated in cardiac myocytes. Takimoto et al have recently shown that RGS2 is a dominating effector of PKG in the myocardium in the initial response to pressure overload . Activation of PKGI-alpha is required for membrane translocation of RGS2 both in vitro and in vivo. Briefly, they have shown that activation of PKGI-alpha alone cannot provide anti-hypertrophic protection unless there is RGS2. Further, inhibition of cGMP-selective PDE5 with sildenafil attenuates pressure overload-induced cardiac hypertrophy in a RGS2-dependent manner. It is noteworthy that the protective effect of PDE5 inhibition has been shown as a direct effect on myocardium rather than a secondary effect of vasodilation.
4.2.3. G-protein-dependent regulation of RGS2 by GC-A-cGMP-PKG axis in the myocardium?
Kangawa and co-workers have recently highlighted the importance of guanylyl cyclase-A (GC-A) in inhibiting cardiac hypertrophy via PKG. It has been shown that hypertrophy itself turns on the hypertrophy gene expression including ANP. Importantly, ANP has been shown to exert anti-hypertrophic effect via stimulating GC-A/PKG-mediated activation of RGS4, which restrains Galphaq/11-coupled hypertrophy signaling. Given that both RGS2 and RGS4 are activated by PKG1-alpha, it is speculated that RGS2 might also be regulated by the Galphaq/11-GC-A-triggered activation of PKG.
4.2.4. Deregulation of the PKG axis - the implications
The aforementioned findings suggest that PKG is crucially involved in regulating RGS2 activity both in the vascular system and in the myocardium, the activation of which attenuates hypertrophy and hypertension via turning down Galphaq/11 signaling. While it is unclear whether PKG activity is also altered in pathophysiological states, clinical studies have shown a marked decrease in expression of endothelial NO synthase (eNOS) and diminished eNOS-mediated NO production in various cardiovascular disease states . Reduced eNOS-NO signaling is expected to cause a defect of the PKG-mediated RGS2 regulation, thus leading to an exacerbated Galphaq/11 signaling and contributing to the progression of cardiovascular diseases.
5. Perspectives
Expression and function of RGS2 is markedly altered in hypertension and hypertensive heart diseases, which is accompanied with exacerbated Galphaq/11 signaling. Given the selective regulation of RGS2 on Galphaq/11, RGS2 appears to be an important candidate as intrinsic suppressor of hypertension and cardiac hypertrophy. In addition, the negative regulation of RGS2 on Galphai/o provides new insights to our understanding of the pathogenesis of HF. Taken together, restoring the expression of RGS2 or increasing its GAP activity in particular and the panel of RGS proteins in general would represent a promising direction in treating major cardiovascular diseases such as hypertension and cardiac hypertrophy and resultant CHF. Understanding the pathophysiology and molecular mechanisms of how RGS2 can turn off maladaptive signals should lead to new insights into pathogenesis and reveal novel therapeutic approaches to treat hypertension and improve the structure and function of the failing heart.
6. Acknowledgements
This work was supported by NIH intramural research grant. There are no relevant conflicts of interest to disclose.
7. References
1. D. Levy, M. G. Larson, R. S. Vasan, W. B. Kannel and K. K. Ho: The progression from hypertension to congestive heart failure. Jama, 275(20), 1557-1562 (1996)
doi:10.1001/jama.275.20.1557
PMid:8622246
2. W. B. Kannel, D. Levy and L. A. Cupples: Left ventricular hypertrophy and risk of cardiac failure: insights from the Framingham Study. J Cardiovasc Pharmacol, 10 Suppl 6, S135-40 (1987)
doi:10.1097/00005344-198706106-00018
PMid:2485019
3. G. L. Jennings: Noradrenaline spillover and microneurography measurements in patients with primary hypertension. J Hypertens Suppl, 16(3), S35-8 (1998)
4. C. Ferrier, M. D. Esler, G. Eisenhofer, B. G. Wallin, M. Horne, H. S. Cox, G. Lambert and G. L. Jennings: Increased norepinephrine spillover into the jugular veins in essential hypertension. Hypertension, 19(1), 62-9 (1992)
5. M. Esler, D. Kaye, G. Lambert, D. Esler and G. Jennings: Adrenergic nervous system in heart failure. Am J Cardiol, 80(11A), 7L-14L (1997)
doi:10.1016/S0002-9149(97)00844-8
PMid:9412538
6. M. R. Bristow: Mechanisms of Development of Heart Failure in the Hypertensive Patient. Cardiology, 92(Suppl. 1), 3-6(1999)
doi:10.1159/000047287
PMid:10652966
7. D. M. Harris, H. I. Cohn, S. Pesant, R.-H. Zhou and A. D. Eckhart: Vascular smooth muscle Gq signaling is involved in high blood pressure in both induced renal and genetic vascular smooth muscle-derived models of hypertension. Am J Physiol Heart Circ Physiol, 293(5), H3072-3079 (2007)
doi:10.1152/ajpheart.00880.2007
PMid:17873012
8. V. LaMorte, J. Thorburn, D. Absher, A. Spiegel, J. Brown, K. Chien, J. Feramisco and K. Knowlton: Gq- and ras-dependent pathways mediate hypertrophy of neonatal rat ventricular myocytes following alpha1-adrenergic stimulation. J. Biol. Chem., 269(18), 13490-13496 (1994)
9. S. A. Akhter, L. M. Luttrell, H. A. Rockman, G. Iaccarino, R. J. Lefkowitz and W. J. Koch: Targeting the Receptor-Gq Interface to Inhibit in Vivo Pressure Overload Myocardial Hypertrophy. Science, 280(5363), 574-577 (1998)
doi:10.1126/science.280.5363.574
PMid:9554846
10. N. Wettschureck, H. Rutten, A. Zywietz, D. Gehring, T. M. Wilkie, J. Chen, K. R. Chien and S. Offermanns: Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Galphaq/Galpha11 in cardiomyocytes. Nat Med, 7(11), 1236-40 (2001)
doi:10.1038/nm1101-1236
PMid:11689889
11. D. D. D' Angelo, Y. Sakata, J. N. Lorenz, G. P. Boivin, R. A. Walsh, S. B. Liggett and G. W. Dorn: Transgenic Gαq overexpression induces cardiac contractile failure in mice.
Proc Natl Acad Sci U S A, 94(15), 8121-8126 (1997)
doi:10.1073/pnas.94.15.8121
12. T. Eschenhagen, U. Mende, M. Nose, W. Schmitz, H. Scholz, A. Haverich, S. Hirt, V. Doring, P. Kalmar, W. Hoppner and et al.: Increased messenger RNA level of the inhibitory G protein alpha subunit Gi alpha-2 in human end-stage heart failure. Circ Res, 70(4), 688-96 (1992)
13. D. S. Feldman, T. S. Elton, B. Sun, M. M. Martin and M. T. Ziolo: Mechanisms of Disease: detrimental adrenergic signaling in acute decompensated heart failure. Nat Clin Pract Cardiovasc Med, 5(4), 208-218 (2008)
doi:10.1038/ncpcardio1127
PMid:18283305 PMCid:2413061
14. O. E. Brodde: Beta-adrenoceptors in cardiac disease. Pharmacol Ther, 60(3), 405-430 (1993)
doi:10.1016/0163-7258(93)90030-H
15. A. M. Feldman, A. E. Cates, W. B. Veazey, R. E. Hershberger, M. R. Bristow, K. L. Baughman, W. A. Baumgartner and C. Van Dop: Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart. J Clin Invest, 82(1), 189-97 (1988)
doi:10.1172/JCI113569
PMid:2839545 PMCid:303493
16. M. C. Hendriks-Balk, S. L. M. Peters, M. C. Michel and A. E. Alewijnse: Regulation of G protein-coupled receptor signalling: Focus on the cardiovascular system and regulator of G protein signalling proteins. Eur J of Pharmacol, 585(2-3), 278-291 (2008)
doi:10.1016/j.ejphar.2008.02.088
PMid:18410914
17. S. Salim, S. Sinnarajah, J. H. Kehrl and C. W. Dessauer: Identification of RGS2 and Type V Adenylyl Cyclase Interaction Sites. J. Biol. Chem., 278(18), 15842-15849 (2003)
doi:10.1074/jbc.M210663200
PMid:12604604
18. P. Vantrimpont, J. L. Rouleau, C.C. Wun, A. Ciampi, M. Klein, B. Sussex, J. M. Arnold, L. Moye and M. Pfeffer: Additive Beneficial Effects of Beta-Blockers to Angiotensin-Converting Enzyme Inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. J Am Coll Cardiol., 29(2), 229-236 (1997)
doi:10.1016/S0735-1097(96)00489-5
PMid:9014971
19. J. Frank: Managing hypertension using combination therapy. Am Fam Physician, 77(9), 1279-86 (2008)
20. C. Rosendorff: Hypertension and coronary artery disease: a summary of the American Heart Association scientific statement. J Clin Hypertens (Greenwich), 9(10), 790-5 (2007)
21. S. Erdine, O. Ari, A. Zanchetti, R. Cifkova, R. Fagard, S. Kjeldsen, G. Mancia, N. Poulter, K. H. Rahn, J. L. Rodicio, L. M. Ruilope, J. Staessen, P. van Zwieten, B. Waeber and B. Williams: ESH-ESC guidelines for the management of hypertension. Herz, 31(4), 331-8 (2006)
doi:10.1007/s00059-006-2829-3
22. K. Wachtell, B. Dahlof, J. Rokkedal, V. Papademetriou, M. S. Nieminen, G. Smith, E. Gerdts, K. Boman, J. N. Bella and R. B. Devereux: Change of left ventricular geometric pattern after 1 year of antihypertensive treatment: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Am Heart J, 144(6), 1057-1064 (2002)
doi:10.1067/mhj.2002.126113
PMid:12486431
23. M. Hartford, I. Wendelhag, G. Berglund, I. Wallentin, S. Ljungman and J. Wikstrand: Cardiovascular and renal effects of long-term antihypertensive treatment. Jama, 259(17), 2553-7 (1988)
doi:10.1001/jama.259.17.2553
PMid:3357228
24. F. G. Dunn, H. O. Ventura, F. H. Messerli, I. Kobrin and E. D. Frohlich: Time course of regression of left ventricular hypertrophy in hypertensive patients treated with atenolol. Circulation, 76(2), 254-8 (1987)
25. M. Shahi, S. Thom, N. Poulter, P. S. Sever and R. A. Foale: Regression of hypertensive left ventricular hypertrophy and left ventricular diastolic function. Lancet, 336(8713), 458-461 (1990)
doi:10.1016/0140-6736(90)92010-F
26. F. G. Dunn, W. Oigman, H. O. Ventura, F. H. Messerli, I. Kobrin and E. D. Frohlich: Enalapril improves systemic and renal hemodynamics and allows regression of left ventricular mass in essential hypertension. Am J Cardiol, 53(1), 105-108 (1984)
doi:10.1016/0002-9149(84)90692-1
PMid:6318542
27. E. J. Eichhorn, C. M. Heesch, J. H. Barnett, L. G. Alvarez, S. M. Fass, P. A. Grayburn, B. A. Hatfield, L. G. Marcoux and C. R. Malloy: Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol, 24(5), 1310-20 (1994)
28. R. Adorisio, L. De Luca, J. Rossi and M. Gheorghiade: Pharmacological treatment of chronic heart failure. Heart Fail Rev, 11(2), 109-123 (2006)
doi:10.1007/s10741-006-9482-z
PMid:16937030
29. A. D. Lopez and C. D. Mathers: Measuring the global burden of disease and epidemiological transitions: 20022030. Ann Trop Med Parasitol, 100, 481-499 (2006)
doi:10.1179/136485906X97417
PMid:16899150
30. A. D. Lopez, C. D. Mathers, M. Ezzati, D. T. Jamison and C. J. L. Murray: Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet, 367(9524), 1747-1757 (2001)
doi:10.1016/S0140-6736(06)68770-9
31. L. D. Adams, R. L. Geary, B. McManus and S. M. Schwartz: A Comparison of Aorta and Vena Cava Medial Message Expression by cDNA Array Analysis Identifies a Set of 68 Consistently Differentially Expressed Genes, All in Aortic Media. Circ Res, 87(7), 623-631 (2000)
32. C. Mittmann, C. H. Chung, G. Hoppner, C. Michalek, M. Nose, C. Schuler, A. Schuh, T. Eschenhagen, J. Weil, B. Pieske, S. Hirt and T. Wieland: Expression of ten RGS proteins in human myocardium: functional characterization of an upregulation of RGS4 in heart failure. Cardiovasc Res, 55(4), 778-786 (2002)
doi:10.1016/S0008-6363(02)00459-5
PMid:12176127
33. H. Cho, K. Harrison, O. Schwartz and J. H. Kehrl: The aorta and heart differentially express RGS (regulators of G-protein signalling) proteins that selectively regulate sphingosine 1-phosphate, angiotensin II and endothelin-1 signalling. Biochem. J., 371(3), 973-980 (2003)
doi:10.1042/BJ20021769
PMid:12564955 PMCid:1223344
34. J. Hao, C. Michalek, W. Zhang, M. Zhu, X. Xu and U. Mende: Regulation of cardiomyocyte signaling by RGS proteins: Differential selectivity towards G proteins and susceptibility to regulation. J Mol Cell Cardiol, 41(1), 51-61 (2006)
doi:10.1016/j.yjmcc.2006.04.003
PMid:16756988
35. S. Zhang, N. Watson, J. Zahner, J. N. Rottman, K. J. Blumer and A. J. Muslin: RGS3 and RGS4 are GTPase Activating Proteins in the Heart. J Mol Cell Cardiol, 30(2), 269-276 (1998)
doi:10.1006/jmcc.1997.0591
PMid:9515003
36. S. P. Heximer, N. Watson, M. E. Linder, K. J. Blumer and J. R. Hepler: RGS2/G0S8 is a selective inhibitor of Gqalpha function. Proc Natl Acad Sci U S A, 94(26), 14389-14393 (1997)
doi:10.1073/pnas.94.26.14389
37. S. P. Heximer, S. P. Srinivasa, L. S. Bernstein, J. L. Bernard, M. E. Linder, J. R. Hepler and K. J. Blumer: G Protein Selectivity Is a Determinant of RGS2 Function. J. Biol. Chem., 274(48), 34253-34259 (1999)
doi:10.1074/jbc.274.48.34253
PMid:10567399
38. A. Semplicini, L. Lenzini, M. Sartori, I. Papparella, L. A. Calo, E. Pagnin, G. Strapazzon, C. Benna, R. Costa, A. Avogaro, G. Ceolotto and A. C. Pessina: Reduced expression of regulator of G-protein signaling 2 (RGS2) in hypertensive patients increases calcium mobilization and ERK1/2 phosphorylation induced by angiotensin II. J Hypertens, 24(6), 1115-24 (2006)
doi:10.1097/01.hjh.0000226202.80689.8f
PMid:16685213
39. J. Yang, K. Kamide, Y. Kokubo, S. Takiuchi, C. Tanaka, M. Banno, Y. Miwa, M. Yoshii, T. Horio, A. Okayama, H. Tomoike, Y. Kawano and T. Miyata: Genetic variations of regulator of G-protein signaling 2 in hypertensive patients and in the general population. J Hypertens, 23(8), 1497-505 (2005)
doi:10.1097/01.hjh.0000174606.41651.ae
PMid:16003176
40. L. A. Calo, E. Pagnin, P. A. Davis, M. Sartori, G. Ceolotto, A. C. Pessina and A. Semplicini: Increased Expression of Regulator of G Protein Signaling-2 (RGS-2) in Bartter's/Gitelman's Syndrome. A Role in the Control of Vascular Tone and Implication for Hypertension. J Clin Endocrinol Metab, 89(8), 4153-4157 (2004)
doi:10.1210/jc.2004-0498
41. S. P. Heximer, R. H. Knutsen, X. Sun, K. M. Kaltenbronn, M. H. Rhee, N. Peng, A. Oliveira-dos-Santos, J. M. Penninger, A. J. Muslin, T. H. Steinberg, J. M. Wyss, R. P. Mecham and K. J. Blumer: Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J Clin Invest, 111(4), 445-52 (2003)
doi:10.1172/JCI15598
PMid:12588882 PMCid:151918
42. K. M. Tang, G. R. Wang, P. Lu, R. H. Karas, M. Aronovitz, S. P. Heximer, K. M. Kaltenbronn, K. J. Blumer, D. P. Siderovski, Y. Zhu and M. E. Mendelsohn: Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med, 9(12), 1506-12 (2003)
doi:10.1038/nm958
PMid:14608379
43. E. Takimoto, N. Koitabashi, S. Hsu, E. A. Ketner, M. Zhang, T. Nagayama, D. Bedja, K. L. Gabrielson, R. Blanton, D. P. Siderovski, M. E. Mendelsohn and D. A. Kass: Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J Clin Invest, 119(2), 408-20 (2009)
44. W. Zhang, T. Anger, J. Su, J. Hao, X. Xu, M. Zhu, A. Gach, L. Cui, R. Liao and U. Mende: Selective Loss of Fine Tuning of Gq/11 Signaling by RGS2 Protein Exacerbates Cardiomyocyte Hypertrophy. J. Biol. Chem., 281(9), 5811-5820 (2006)
doi:10.1074/jbc.M507871200
PMid:16380388
45. M. X. Zou, A. A. Roy, Q. Zhao, L. A. Kirshenbaum, M. Karmazyn and P. Chidiac: RGS2 is upregulated by and attenuates the hypertrophic effect of alpha1-adrenergic activation in cultured ventricular myocytes. Cell Signal 18(10), 1655-1663 (2006)
doi:10.1016/j.cellsig.2006.01.012
PMid:16517124
46. W. B. Kannel: Incidence and Epidemiology of Heart Failure. Heart Fail Rev, 5(2), 167-173 (2000)
doi:10.1023/A:1009884820941
PMid:16228142
47. S. L. Grant, B. Lassegue, K. K. Griendling, M. Ushio-Fukai, P. R. Lyons and R. W. Alexander: Specific Regulation of RGS2 Messenger RNA by Angiotensin II in Cultured Vascular Smooth Muscle Cells. Mol Pharmacol, 57(3), 460-467 (2000)
48. E. L. Riddle, B. K. Rana, K. K. Murthy, F. Rao, E. Eskin, D. T. O'Connor and P. A. Insel: Polymorphisms and Haplotypes of the Regulator of G Protein Signaling-2 Gene in Normotensives and Hypertensives. Hypertension, 47(3), 415-420 (2006)
doi:10.1161/01.HYP.0000200714.81990.61
PMid:16432041
49. M. Lelonek, T. Pietrucha, M. Matyjaszczyk and J. H. Goch: Polymorphism C1114G of Gene Encoding the Cardiac Regulator of G-Protein Signaling 2 May Be Associated with Number of Episodes of Neurally Mediated Syncope. Archives of Medical Research, 40(3), 191-195 (2009)
doi:10.1016/j.arcmed.2009.02.005
PMid:19427970
50. X. Sun, K. M. Kaltenbronn, T. H. Steinberg and K. J. Blumer: RGS2 Is a Mediator of Nitric Oxide Action on Blood Pressure and Vasoconstrictor Signaling. Mol Pharmacol, 67(3), 631-639 (2005)
doi:10.1124/mol.104.007724
PMid:15563583
51. L. A. Calo, E. Pagnin, G. Ceolotto, P. A. Davis, S. Schiavo, I. Papparella, A. Semplicini and A. C. Pessina: Silencing regulator of G protein signaling-2 (RGS-2) increases angiotensin II signaling: insights into hypertension from findings in Bartter's/Gitelman's syndromes. J Hypertens, 26(5), 938-45 (2008)
doi:10.1097/HJH.0b013e3282f60d98
PMid:18398336
52. A. Wirth, Z. Benyo, M. Lukasova, B. Leutgeb, N. Wettschureck, S. Gorbey, P. Orsy, B. Horvath, C. Maser-Gluth, E. Greiner, B. Lemmer, G. Schutz, S. Gutkind and S. Offermanns: G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat Med, 14(1), 64-68 (2008)
doi:10.1038/nm1666
PMid:18084302
53. W. Grossman, D. Jones and L. P. McLaurin: Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest, 56(1), 56-64 (1975)
doi:10.1172/JCI108079
PMid:124746 PMCid:436555
54. A. Diwan and G. W. Dorn, II: Decompensation of Cardiac Hypertrophy: Cellular Mechanisms and Novel Therapeutic Targets. Physiology, 22(1), 56-64 (2007)
doi:10.1152/physiol.00033.2006
PMid:17289931
55. F. H. Messerli and T. Grodzicki: Hypertension, left ventricular hypertrophy, ventricular arrhythmias and sudden death. Eur Heart J, 13 Suppl D, 66-9 (1992)
56. B. H. Lorell: Transition from hypertrophy to failure. Circulation, 96(11), 3824-7 (1997)
57. U. Mende, A. Kagen, A. Cohen, J. Aramburu, F. J. Schoen and E. J. Neer: Transient cardiac expression of constitutively active Galphaq leads to hypertrophy and dilated cardiomyopathy by calcineurin-dependent and independent pathways. Proc Natl Acad Sci U S A, 95(23), 13893-13898 (1998)
doi:10.1073/pnas.95.23.13893
58. J. R. Keys, E. A. Greene, W. J. Koch and A. D. Eckhart: Gq-Coupled Receptor Agonists Mediate Cardiac Hypertrophy Via the Vasculature. Hypertension, 40(5), 660-666 (2002)
doi:10.1161/01.HYP.0000035397.73223.CE
PMid:12411459
59. G. Esposito, A. Rapacciuolo, S. V. Naga Prasad and H. A. Rockman: Cardiac hypertrophy: Role of G protein-coupled receptors. J Card Fail, 8(6, Part 2), S409-S414 (2002)
doi:10.1054/jcaf.2002.129283
PMid:12555153
60. G. W. 2nd Dorn, H.S. Hahn: Genetic Factors in Cardiac Hypertrophy. Ann N Y Acad Sci, 1015, 225-237 (2004)
61. C. Hague, L. S. Bernstein, S. Ramineni, Z. Chen, K. P. Minneman and J. R. Hepler: Selective Inhibition of {alpha}1A-Adrenergic Receptor Signaling by RGS2 Association with the Receptor Third Intracellular Loop. J. Biol. Chem., 280(29), 27289-27295 (2005)
doi:10.1074/jbc.M502365200
PMid:15917235
62. J. D. Molkentin, J. R. Lu, C. L. Antos, B. Markham, J. Richardson, J. Robbins, S. R. Grant and E. N. Olson: A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy. Cell, 93(2), 215-228 (1998)
doi:10.1016/S0092-8674(00)81573-1
PMid:9568714
63. P. Tamirisa, K. J. Blumer and A. J. Muslin: RGS4 Inhibits G-Protein Signaling in Cardiomyocytes. Circulation, 99(3), 441-447 (1999)
64. J. H. Rogers, A. Tsirka, A. Kovacs, K. J. Blumer, G. W. Dorn and A. J. Muslin: RGS4 Reduces Contractile Dysfunction and Hypertrophic Gene Induction in Gαq Over-expressing Mice. J Mol Cell Cardiol, 33(2), 209-218 (2001)
doi:10.1006/jmcc.2000.1307
PMid:11162127
65. T. Tokudome, I. Kishimoto, T. Horio, Y. Arai, D. O. Schwenke, J. Hino, I. Okano, Y. Kawano, M. Kohno, M. Miyazato, K. Nakao and K. Kangawa: Regulator of G-Protein Signaling Subtype 4 Mediates Antihypertrophic Effect of Locally Secreted Natriuretic Peptides in the Heart. Circulation, 117(18), 2329-2339 (2008)
doi:10.1161/CIRCULATIONAHA.107.732990
PMid:18443239
66. K. Tojo, S. Sato, G. Tokudome, M. Ohta, Y. Kawaguchi, O. Sakai, O. Nakagawa and K. Nakao: Stimulation by Corticotropin-Releasing Factor of Atrial Natriuretic Peptide and Brain Natriuretic Peptide Secretions from Cultured Neonatal Rat Cardiomyocytes. Biochem Biophys Res Commun, 225(2), 340-346 (1996)
doi:10.1006/bbrc.1996.1177
PMid:8753766
67. J. H. Rogers, P. Tamirisa, A. Kovacs, C. Weinheimer, M. Courtois, K. J. Blumer, D. P. Kelly and A. J. Muslin: RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload. J Clin Invest, 104(5), 567-76 (1999)
doi:10.1172/JCI6713
PMid:10487771 PMCid:408537
68. W. B. Kannel, W. P. Castelli, P. M. McNamara, P. A. McKee and M. Feinleib: Role of blood pressure in the development of congestive heart failure. The Framingham study. N Engl J Med, 287(16), 781-7 (1972)
69. G. Esposito, A. Rapacciuolo, S. V. Naga Prasad, H. Takaoka, S. A. Thomas, W. J. Koch and H. A. Rockman: Genetic Alterations That Inhibit In Vivo Pressure-Overload Hypertrophy Prevent Cardiac Dysfunction Despite Increased Wall Stress. Circulation, 105(1), 85-92 (2002)
doi:10.1161/hc0102.101365
PMid:11772881
70. S. V. Prasad, J. Nienaber and H. A. Rockman: G-protein-coupled receptor function in heart failure. Cold Spring Harb Symp Quant Biol, 67, 439-44 (2002)
doi:10.1101/sqb.2002.67.439
PMid:12858569
71. R. P. Xiao, S. J. Zhang, K. Chakir, P. Avdonin, W. Z. Zhu, R. A. Bond, C. W. Balke, E. G. Lakatta and H. P. Cheng: Enhanced Gi signaling selectively negates 2-adrenergic receptor (AR)- but not 1-AR-mediated positive inotropic effect in myocytes from failing rat hearts. Circulation, 108(13), 1633-1639 (2003)
doi:10.1161/01.CIR.0000087595.17277.73
PMid:12975249
72. A. A. Roy, A. Baragli, L. S. Bernstein, J. R. Hepler, T. E. Hebert and P. Chidiac: RGS2 interacts with Gs and adenylyl cyclase in living cells. Cell Signal, 18(3), 336-348 (2006)
doi:10.1016/j.cellsig.2005.05.004
PMid:16095880
73. V. J. Owen, P. B. J. Burton, A. J. Mullen, E. J. Birks, P. Barton and M. H. Yacoub: Expression of RGS3, RGS4 and Gi alpha 2 in acutely failing donor hearts and end-stage heart failure. Eur Heart J, 22(12), 1015-1020 (2001)
doi:10.1053/euhj.2000.2578
PMid:11428836
74. Y. Takeishi, T. Jalili, B. D. Hoit, D. L. Kirkpatrick, L. E. Wagoner, W. T. Abraham and R. A. Walsh: Alterations in Ca2+ cycling proteins and G?q signaling after left ventricular assist device support in failing human hearts. Cardiovasc Res, 45(4), 883-888 (2000)
doi:10.1016/S0008-6363(99)00415-0
PMid:10728414
75. Y. Li, S. Hashim and M. B. Anand-Srivastava: Angiotensin II-evoked enhanced expression of RGS2 attenuates Gi-mediated adenylyl cyclase signaling in A10 cells. Cardiovasc Res, 66(3), 503-511 (2005)
doi:10.1016/j.cardiores.2005.02.005
PMid:15914115
76. P. A. Insel and R. S. Ostrom: Forskolin as a Tool for Examining Adenylyl Cyclase Expression, Regulation, and G Protein Signaling. Cell Mol Neurobiol, 23, 305-314 (2003)
doi:10.1023/A:1023684503883
PMid:12825829
77. D. J. Pepperl, S. Shah-Basu, D. VanLeeuwen, J. G. Granneman and R. G. MacKenzie: Regulation of RGS mRNAs by cAMP in PC12 Cells. Biochem Biophys Res Commun, 243(1), 52-55 (1998)
doi:10.1006/bbrc.1997.8056
PMid:9473478
78. P. Osei-Owusu, X. Sun, R. M. Drenan, T. H. Steinberg and K. J. Blumer: Regulation of RGS2 and Second Messenger Signaling in Vascular Smooth Muscle Cells by cGMP-dependent Protein Kinase. J. Biol. Chem., 282(43), 31656-31665 (2007)
doi:10.1074/jbc.M706360200
PMid:17681944
79. L. Kalinowski, I. T. Dobrucki and T. Malinski: Race-Specific Differences in Endothelial Function: Predisposition of African Americans to Vascular Diseases. Circulation, 109(21), 2511-2517 (2004)
doi:10.1161/01.CIR.0000129087.81352.7A
PMid:15159296
80. T. Munzel, S. Genth-Zotz and U. Hink: Targeting Heme-Oxidized Soluble Guanylate Cyclase: Solution for All Cardiorenal Problems in Heart Failure? Hypertension, 49(5), 974-976 (2007)
doi:10.1161/HYPERTENSIONAHA.106.085456
PMid:17325236
81. T. Malinski: Understanding Nitric Oxide Physiology in the Heart: A Nanomedical Approach. Am J Cardiol, 96(7,Supplement 2), 13-24 (2005)
doi:10.1016/j.amjcard.2005.07.029
PMid:15979424
82. M. Dupuis, F. Soubrier, I. Brocheriou, S. Raoux, M. Haloui, L. Louedec, J.-B. Michel and S. Nadaud: Profiling of Aortic Smooth Muscle Cell Gene Expression in Response to Chronic Inhibition of Nitric Oxide Synthase in Rats. Circulation, 110(7), 867-873 (2004)
doi:10.1161/01.CIR.0000138850.72900.FE
PMid:15289382
Key Words: GPCR signaling, regulator of G-protein signaling, cardiovascular system, review
Send correspondence to: Rui-Ping Xiao, Laboratory of Cardiovascular Science, NIA, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, Tel: 410-558-8662, Fax: 410-558-8150, E-mail:Xiaor@grc.nia.nih.gov