Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signaling by hormones and neurotransmitters that activate G protein-coupled receptors (GPCRs) maintains blood pressure within the normal range despite large changes in cardiac output that can occur within seconds. This implies that blood pressure regulation requires precise kinetic control of GPCR signaling. To test this hypothesis, we analyzed mice deficient in RGS2, a GTPase-activating protein that greatly accelerates the deactivation rate of heterotrimeric G proteins in vitro. Both rgs2+/- and rgs2-/- mice exhibited a strong hypertensive phenotype, renovascular abnormalities, persistent constriction of the resistance vasculature, and prolonged response of the vasculature to vasoconstrictors in vivo. Analysis of P2Y receptor-mediated Ca2+ signaling in vascular smooth muscle cells in vitro indicated that loss of RGS2 increased agonist potency and efficacy and slowed the kinetics of signal termination. These results establish that abnormally prolonged signaling by G protein-coupled vasoconstrictor receptors can contribute to the onset of hypertension, and they suggest that genetic defects affecting the function or expression of RGS2 may be novel risk factors for development of hypertension in humans.
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PMID:Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. 1269 45

Plasma adenosine levels are elevated in cardiovascular disease including hypertension and heart failure, and the nucleoside has been proposed to serve as an endogenous antimyocardial remodeling factor. We studied the modulation of phenylephrine-induced hypertrophy by adenosine receptor activation in isolated neonatal cultured ventricular myocytes. Phenylephrine (10 muM) increased cell size by 35% and significantly increased expression of atrial natriuretic peptide. These effects were reduced by the stable adenosine analog 2-chloroadenosine and were completely blocked by the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (1 microM), the A(2A) receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine (100 nM), and the A(3) receptor agonist N(6)-(3-iodobenzyl)adenosine-5'-methyluronamide (100 nM). The antihypertrophic effects of all three agonists were completely reversed by their respective antagonists. Phenylephrine significantly up-regulated expression of the immediate early gene c-fos especially within the first 30 min of phenylephrine treatment. These effects were almost completely inhibited by all adenosine receptor agonists. Although phenylephrine also induced early stimulation of both p38 mitogen-activated protein kinase and extracellular signal-regulated kinase, these responses were unaffected by adenosine agonists. The expression of the G-protein regulatory factors RGS2 and RGS4 were increased by nearly 3-fold by phenylephrine treatment although this was completely prevented by adenosine receptor agonists. These agents also blocked the ability of phenylephrine to up-regulate Na/H exchange isoform 1 (NHE1) expression in hypertrophied myocytes. Thus, our results demonstrate an antihypertrophic effect of adenosine acting via multiple receptor subtypes through a mechanism involving down-regulation of NHE1 expression. The ability to prevent regulators of G-protein signaling (RGS) up-regulation further suggests that adenosine receptor activation minimizes signaling which leads to hypertrophic responses.
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PMID:Inhibition of phenylephrine-induced cardiomyocyte hypertrophy by activation of multiple adenosine receptor subtypes. 1545 91

The nitric oxide (NO)-cGMP pathway regulates vascular tone and blood pressure by mechanisms that are incompletely understood. RGS2, a GTPase-activating protein for Gqalpha that is critical for blood pressure homeostasis, has been suggested to serve as an effector of the NO-cGMP pathway that promotes vascular relaxation based on studies of aortic rings in vitro. To test this hypothesis and its relevance to blood pressure control, we determined whether RGS2 functions as an NO effector in smooth muscle of the resistance vasculature. We report that 1) the ability of the NO donor sodium nitroprusside to reduce blood pressure is impaired in RGS2-/- mice, 2) vasopressin-triggered Ca2+ transients are augmented in smooth muscle cells from resistance arteries of RGS2-/- mice, and 3) cGMP analogs fail to inhibit vasopressin-triggered Ca2+ transients in smooth muscle cells from resistance arteries of RGS2-/- mice even though cGMP-dependent protein kinase (PKG)1alpha and PKG1beta are expressed and activated normally. These results indicated that the NO-cGMP pathway uses RGS2 as a novel downstream effector to promote vascular relaxation by attenuating vasoconstrictor-triggered Ca2+ signaling in vascular smooth muscle cells. Genetic or epigenetic impairment of this mechanism may contribute to the development of hypertension, and augmenting it pharmacologically may provide a novel means of treating this disease.
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PMID:RGS2 is a mediator of nitric oxide action on blood pressure and vasoconstrictor signaling. 1556 83

Regulator of G protein signaling (RGS) proteins stimulate the GTPase activity of Galpha subunits of heterotrimeric G proteins, thereby negatively regulating G protein-coupled receptor signaling. RGS2, which preferentially alters Galphaq-mediated signaling, may be important for cardiovascular health, because knockout of RGS2 in mice is associated with altered smooth muscle relaxation and hypertension. In this study, we determined genetic variation in the human RGS2 gene by sequencing DNA in normotensive and hypertensive populations of whites (n=128) and blacks (n=122). We identified 14 single nucleotide polymorphisms and 2 two-base insertion/deletions (in/del; 1891 to 1892 TC and 2138 to 2139 AA). Although most of the genetic variants were found at low allelic frequency, in particular in coding regions, the 1891 to 1892 TC and 2138 to 2139 AA intronic in/del were in linkage disequilibrium and were associated with hypertension in blacks (P<0.05). We defined several haplotypes for the RGS2 gene, certain of which showed striking differences between whites and blacks. Additionally, 2 haplotypes had significantly different frequencies between hypertensive and normotensive black groups (P<0.05). We conclude that RGS2 is genetically conserved within coding regions but that the intronic in/del define ethnicity-specific haplotypes. Moreover, certain RGS2 variants that occur at greater frequency in hypertensive blacks may serve as ethnicity-specific genetic variants for this disease.
Hypertension 2006 Mar
PMID:Polymorphisms and haplotypes of the regulator of G protein signaling-2 gene in normotensives and hypertensives. 1643 40

Regulator of G protein signaling (RGS) proteins modulate G protein-coupled receptor (GPCR) signaling. The N termini of some RGS4-family proteins provide receptor specificity and also contain an N-end rule determinant that results in ubiquitylation and decreased protein expression. The relevance of these mechanisms to other RGS proteins is not fully understood. Thus we examined function, receptor specificity, and expression of R4 subfamily RGS proteins (RGS2, -3, -4, -5, and -8). Although the N terminus plays a key role in protein stability in human embryonic kidney (HEK) 293 cells, we were unable to demonstrate specificity of RGS2, -3, -4, -5, or -8 for muscarinic receptors (M(1), M(3), and M(5)). However, cellular RGS activity (8 = 3 > 2) was strongly correlated with expression; RGS4 and -5 had minimal expression and activity. Stabilizing mutations of RGS4 and -5 (C2S) enhanced expression and function with a greater influence on RGS4 than on RGS5. We were surprised to find that a predicted destabilizing mutation in RGS8 (A2C) did not markedly affect expression and had no effect on function. In contrast, a destabilizing mutation in RGS2 (RGS2-Q2L) recently identified as a rare N-terminal genetic variant in a Japanese hypertensive cohort (J Hypertens 23:1497-1505, 2005) showed significantly reduced expression and inhibition of angiotensin II (AT(1)) receptor-stimulated accumulation of inositol phosphates. We were surprised to find that RGS2-Q2R, also predicted to be destabilizing, showed nearly normal expression and function. Thus, proteasomal regulation of RGS expression in HEK293 cells strongly controls RGS function and a novel RGS2 mutation with decreased protein expression could be relevant to the pathophysiology of hypertension in humans.
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PMID:N-terminal residues control proteasomal degradation of RGS2, RGS4, and RGS5 in human embryonic kidney 293 cells. 1722 Mar 56

Rgs2 (regulator of G-protein signaling-2)-deficient mice exhibit severe hypertension, and genetic variations of RGS2 occur in hypertensive patients. RGS2 mRNA up-regulation by angiotensin II (Ang II) in vascular smooth muscle cells (VSMC) is a potentially important negative feedback mechanism in blood pressure homeostasis, but how it occurs is unknown. Here we demonstrate that group VIA phospholipase A2 (iPLA2beta) plays a pivotal role in Ang II-induced RGS2 mRNA up-regulation in VSMC by three independent approaches, including pharmacologic inhibition with a bromoenol lactone suicide substrate, suppression of iPLA2beta expression with antisense oligonucleotides, and genetic deletion in iPLA2beta-null mice. Selective inhibition of iPLA2beta by each of these approaches abolishes Ang II-induced RGS2 mRNA up-regulation. Furthermore, using adenovirus-mediated gene transfer, we demonstrate that restoration of iPLA2beta-expression in iPLA2beta-null VSMC reconstitutes the ability of Ang II to up-regulate RGS2 mRNA expression. In contrast, Ang II-induced vasodilator-stimulated phosphoprotein phosphorylation and Ang II receptor expression are unaffected. Moreover, in wild-type but not iPLA2beta-null VSMC, Ang II stimulates iPLA2 enzymatic activity significantly. Both arachidonic acid and lysophosphatidylcholine, products of iPLA2beta action, induce RGS2 mRNA up-regulation. Inhibition of lipoxygenases, particularly 15-lipoxygenase, and cyclooxygenases, but not cytochrome P450-dependent epoxygenases inhibits Ang II- or AA-induced RGS2 mRNA expression. Moreover, RGS2 protein expression is also up-regulated by Ang II, and this is attenuated by bromoenol lactone. Disruption of the Ang II/iPLA2beta/RGS2 feedback pathway in iPLA2beta-null cells potentiates Ang II-induced vasodilator-stimulated phosphoprotein and Akt phosphorylation in a time-dependent manner. Collectively, our results demonstrate that iPLA2beta participates in Ang II-induced transcriptional up-regulation of RGS2 in VSMC.
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PMID:Group VIA phospholipase A2 (iPLA2beta) participates in angiotensin II-induced transcriptional up-regulation of regulator of g-protein signaling-2 in vascular smooth muscle cells. 1761 34

RGS2, a GTPase-activating protein (GAP) for G(q)alpha, regulates vascular relaxation and blood pressure. RGS2 can be phosphorylated by type Ialpha cGMP-dependent protein kinase (cGKIalpha), increasing its GAP activity. To understand how RGS2 and cGKIalpha regulate vascular smooth muscle signaling and function, we identified signaling pathways that are controlled by cGMP in an RGS2-dependent manner and discovered new mechanisms whereby cGK activity regulates RGS2. We show that RGS2 regulates vasoconstrictor-stimulated Ca(2+) store release, capacitative Ca(2+) entry, and noncapacitative Ca(2+) entry and that RGS2 is required for cGMP-mediated inhibition of vasoconstrictor-elicited phospholipase Cbeta activation, Ca(2+) store release, and capacitative Ca(2+) entry. RGS2 is degraded in vascular smooth muscle cells via the proteasome. Inhibition of cGK activity blunts RGS2 degradation. However, inactivation of the cGKIalpha phosphorylation sites in RGS2 does not stabilize the protein, suggesting that cGK activity regulates RGS2 degradation by other mechanisms. cGK activation promotes association of RGS2 with the plasma membrane by a mechanism requiring its cGKIalpha phosphorylation sites. By regulating GAP activity, plasma membrane association, and degradation, cGKIalpha therefore may control a cycle of RGS2 activation and inactivation. By diminishing cGK activity, endothelial dysfunction may impair RGS2 activation, thereby blunting vascular relaxation and contributing to hypertension.
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PMID:Regulation of RGS2 and second messenger signaling in vascular smooth muscle cells by cGMP-dependent protein kinase. 1768 44

Overexpression of regulator of G protein signaling 5 (RGS5) in arteries over veins is the most striking difference observed using microarray analysis. The obvious question is what arterial function might require RGS5. Based on functions of homologous proteins in regulating cardiac mass and G-protein-coupled receptor (GPCR) signaling, we proposed that RGS5 and vascular expressed RGS2 and RGS4 could participate in regulating arterial hypertrophy. We used the suprarenal abdominal aorta banding model to induce hypertension and hypertrophy. All 3 RGS messages were expressed in unmanipulated aorta with RGS5 predominating. After 2 days, thoracic aorta lost expression of RGS5, 4, and 2. At 1 week, all three returned to normal, and at 28 days, they increased many fold above normal. Valsartan blockade of angiotensin II (angII)/angII type 1 receptor signaling prevented upregulation of RGS messages but only delayed mass increases, implying wall mass regulation involves both angII-dependent and angII-independent pathways. The abdominal aorta showed less dramatic expression changes in RGS5 and 4, but not 2. Again, those changes were delayed by valsartan treatment with no mass changes. Thoracic aorta contraction to GPCR agonists was examined in aortic explant rings to identify vessel wall physiological changes. In 2-day aorta, the response to Galphaq/i agonists increased above normal, while 28-day aorta had attenuated induced contraction via Galphaq/i agonist, implicating a connection between RGS message levels and changes in GPCR-induced contraction. In vitro overexpression studies showed RGS5 inhibits angII-induced signaling in smooth muscle cells. This study is the first experimental evidence that changes in RGS expression and function correlate with vascular remodeling.
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PMID:RGS5, RGS4, and RGS2 expression and aortic contractibility are dynamically co-regulated during aortic banding-induced hypertrophy. 1820 59

Hypertension is a leading risk factor for the development of cardiovascular disease. Data from human and animal studies suggest that RGS2, a potent inhibitor of G(q) signaling, is important for blood pressure regulation. Several RGS2 mutations in the Japanese population have been found to be associated with hypertension. The product of one of these alleles, R44H, is mutated within the amino terminal amphipathic alpha-helix domain, the region responsible for plasma membrane-targeting. The functional consequence of this mutation and its potential link to the development of hypertension, however, are not known. In this study, we showed that R44H was a weaker inhibitor of receptor-mediated G(q) signaling than wild-type RGS2. Confocal microscopy revealed that YFP-tagged R44H bound to the plasma membrane less efficiently than wild-type RGS2. R44 is one of the basic residues positioned to stabilize lipid bilayer interaction of the RGS2 amphipathic helix domain. Tryptophan fluorescence and circular dichroism studies of this domain showed that the R44H mutation prevented proper entrenchment of hydrophobic residues into the lipid bilayer without disrupting helix-forming capacity. Together, these data suggest that decreasing the side-chain length and flexibility at R44 prevented proper lipid bilayer association and function of RGS2. Finally, the R44H protein did not behave as a dominant-negative interfering mutant. Thus, our data are consistent with the notion that a R44H missense mutation in human RGS2 produces a hypomorphic allele that may lead to altered receptor-mediated G(q) inhibition and contribute to the development of hypertension in affected subjects.
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PMID:The RGS2 gene product from a candidate hypertension allele shows decreased plasma membrane association and inhibition of Gq. 1823 Jul 14

RGS2 is a negative regulator of Galpha protein signaling and promotes adipocyte differentiation. Recently, we described a polymorphism at the C1114G locus with the G allele associated with hypertension in a cross-sectional study. The aim of the present study was to assess whether the RGS2 C1114G is predictive of overweight in young subjects with grade I hypertension. We genotyped at the RGS2 C1114G locus 406 (male, n = 294; female, n = 112) white hypertensive subjects (age, 33 +/- 9 years) never treated for hypertension and at low cardiovascular risk. Median follow-up was 7.85 years. At baseline, male patients carrying the RGS2 1114G allele had higher body mass index (BMI) than patients with CC genotype (26.1 +/- 0.3 vs 25.3 +/- 0.3 kg/m2, P < .05). The frequency of male patients with BMI > or = 25 was similar between the patients with G allele and those with CC genotype (55.1% vs 47.8%, P = not significant). No significant difference between the 2 groups was observed with regard to physical activity, blood pressure, and heart rate. At the end of follow-up, BMI was higher in male patients with G allele compared with patients with CC genotype (26.8 +/- 0.3 vs 25.8 +/- 0.2 kg/m2, P < .01); and the frequency of male patients with BMI >25 kg/m2 was greater in the former (69.0% vs 52.2%, P < .01). According to Cox regression, allele G was a significant predictor of developing overweight or obesity during follow-up. These epidemiologic relations were not significant in female patients. In young male patients with grade I hypertension, RGS2 1114G allele is associated with increased BMI and with greater risk of developing overweight or obesity. The RGS2 1114G allele may be considered a genetic marker that predicts an individual's predisposition to gaining weight.
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PMID:RGS2 C1114G polymorphism and body weight gain in hypertensive patients. 1824 18


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