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)

Arteries from hypertensive animals and humans have increased spontaneous tone. Increased superoxide anion (superoxide) contributes to elevated blood pressure (BP) and spontaneous tone in hypertension. The association between the extracellular signaling-regulated kinase 1/2 (ERK1/2)-mitogen-activated protein kinase (MAPK) signaling pathway and generation of superoxide and spontaneous tone in isolated aorta was studied in angiotensin II (ANG II)-infused hypertensive (HT) rats. Systolic BP, phosphorylation of ERK, aortic superoxide formation, and aortic spontaneous tone were compared in sham normotensive and HT rats. Infusion of ANG II (0.5 mg x kg(-1) x day(-1) for 6 days) significantly elevated the systolic BP (P<0.01). The phosphorylation of ERK1/2 vs. total ERK1/2 in thoracic aorta was enhanced, and superoxide was increased in the HT vs. the sham group (P<0.01). Spontaneous tone developed in the HT group, but not in the normotensive group. MAPK/ERK1/2 (MEK1/2)-ERK1/2 signaling pathway inhibitors, PD-98059 (10 micromol/l), and U-0126 (10 micromol/l), significantly reduced the phosphorylation of ERK1/2, superoxide generation (P<0.01), and spontaneous tone (P<0.01) in HT. These findings suggest that ANG II infusion induces the production of superoxide and spontaneous tone and that both are dependent on ERK-MAPK activation. In endothelium-denuded aorta, however, MEK1/2 inhibitors did not inhibit the spontaneous tone, even though they significantly reduced superoxide generation similar to endothelium-intact aorta. These data suggest that inhibition of ERK1/2 signaling pathway, via PD-98059 or U-0126, may regulate spontaneous tone in an endothelium-dependent manner. In conclusion, these findings support the importance of the ERK1/2 signaling pathway in modulating vascular oxidative stress and subsequently mediating spontaneous tone in HT.
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PMID:ERK activation contributes to regulation of spontaneous contractile tone via superoxide anion in isolated rat aorta of angiotensin II-induced hypertension. 1730 7

To further elucidate the molecular mechanisms involved in hypertensive vascular remodeling, an immunohistochemical technique and Western blot were applied to study phospho-extracellular signal-regulated kinase (ERK1/2) and transforming growth factor beta1 (TGF-beta1) expression in endothelial and vascular smooth muscle cell (VSMC) of the thoracic aorta and renal arterioles from SHR of different ages. Results of both the immunohistochemistry and Western blot assays showed that either the phospho-ERK1/2 at endothelium or VSMC of renal small arteries from SHR8, SHR16, and SHR20 groups and of the aorta from SHR16 and SHR20 were higher than that from control group. Comparing with that in the small arteries of the kidney, the phospho-ERK1/2 in the endothelium and in VSMC was markedly increased in the aorta, and high expression of TGF-beta1 was detected in the aorta and kidney from SHR16 and SHR20 by Western blot. These results suggested that ERK 1/2 could be activated by phosphorylation with over-expression of TGF-beta1 in the endothelium and in VSMC of aorta and renal arterioles from SHR, which might play an important role in VSMC proliferation under hypertension.
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PMID:High-expression of transforming growth factor beta1 and phosphorylation of extracellular signal-regulated protein kinase in vascular smooth muscle cells from aorta and renal arterioles of spontaneous hypertension rats. 1736 10

Excessive generation of reactive oxygen species (ROS) has been implicated in the pathogenesis of many diseases, including atherosclerosis, hypertension, and vascular complications of diabetes. However, the precise mechanisms by which ROS contribute to the development of these diseases are not fully characterized. Hydrogen peroxide (H2O2), a ROS, has been shown to activate several signaling protein kinases, such as extracellular signal-regulated kinase (ERK)1/2 and protein kinase B (PKB) in different cell types, notably in vascular smooth muscle cells. Because these pathways regulate cellular mitogenesis, migration, proliferation, survival, and death responses, their aberrant activation has been suggested to be a potential mechanism of ROS-induced pathologies. The upstream elements responsible for H2O2-induced ERK1/2 and PKB activation remain poorly characterized, but a potential role of receptor and nonreceptor protein tyrosine kinases (PTKs) as triggers that initiate such events has been postulated. Therefore, the aim of this review is to highlight the involvement of receptor and nonreceptor PTKs in modulating H2O2-induced ERK1/2 and PKB signaling.
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PMID:Role of receptor and nonreceptor protein tyrosine kinases in H2O2-induced PKB and ERK1/2 signaling. 1740 55

Uric acid is considered a major antioxidant in human blood that may protect against aging and oxidative stress. Despite its proposed protective properties, elevated levels of uric acid are commonly associated with increased risk for cardiovascular disease and mortality. Furthermore, recent experimental studies suggest that uric acid may have a causal role in hypertension and metabolic syndrome. All these conditions are thought to be mediated by oxidative stress. In this study we demonstrate that differentiation of cultured mouse adipocytes is associated with increased production of reactive oxygen species (ROS) and uptake of uric acid. Soluble uric acid stimulated an increase in NADPH oxidase activity and ROS production in mature adipocytes but not in preadipocytes. The stimulation of NADPH oxidase-dependent ROS by uric acid resulted in activation of MAP kinases p38 and ERK1/2, a decrease in nitric oxide bioavailability, and an increase in protein nitrosylation and lipid oxidation. Collectively, our results suggest that hyperuricemia induces redox-dependent signaling and oxidative stress in adipocytes. Since oxidative stress in the adipose tissue has recently been recognized as a major cause of insulin resistance and cardiovascular disease, hyperuricemia-induced alterations in oxidative homeostasis in the adipose tissue might play an important role in these derangements.
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PMID:Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. 1742 37

1. We have isolated a novel human erythrocyte-derived depressing factor (EDDF) that has a significant antihypertensive effect in various rat models of hypertension. The aim of the present study was to examine the mechanisms of action of EDDF on vascular function in two-kidney, one-clip (2K1C) renovascular hypertensive rats. 2. The EDDF was prepared from human erythrocytes. Experiments were performed in 18 male Wistar rats. The vascular ring perfusion assay and a two-photon laser scanning fluorescence microscope (TMP) were used to evaluate the vascular contractile response. The effects of EDDF on phenylephrine (PE)- and noradrenaline (NA)-induced vascular contraction were evaluated in 2K1C hypertensive rats. The proliferation and DNA synthesis in vascular smooth muscle cells (VSMC) were determined using the [3H]-TdR (thymidine) incorporation and 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. Flow cytometry, reverse transcription-polymerase chain reaction and western blots were used to measure cell cycle and apoptotic profiles, platelet-derived growth factor (PDGF)-A expression and the activity of extracellular signal-regulated kinase (ERK)-1/2, as well as the expression of cyclin D1 and cyclin-dependent kinase (CDK) 4. 3. At 10(-5) g/mL, EDDF significantly decreased the PE- and NA-induced hypertensive vascular contraction. In addition, EDDF inhibited DNA synthesis in primary VSMC from 2K1C rats. The mRNA expression of PDGF-A in VSMC was twofold higher in 2K1C rats compared with control rats, whereas EDDF significantly inhibited the increment in PDGF-A mRNA expression. In addition, EDDF inhibited the phosphorylation of ERK1/2 and decreased the expression of cyclin D1 and CDK4; p21 (Cip1) levels were increased after treatment with EDDF. 4. In conclusion, EDDF inhibits VSMC proliferation in 2K1C rats through G0/G1 cell cycle arrest. The effects may be mediated, in part, by enhanced expression of p21 (Cip1) and the inhibition of ERK1/2 phosphorylation and the expression of cyclin D1/CDK4 and PDGF-A.
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PMID:Protective role of a novel erythrocyte-derived depressing factor on blood vessels of renovascular hypertensive rats. 1743 6

Angiotensin (Ang)-(1-7), acting through the Mas receptor, opposes the actions of Ang II. Molecular mechanisms for this are unclear. Here we sought to determine whether Ang-(1-7) influences Ang II signaling in human endothelial cells, focusing specifically on Src homology 2-containing inositol phosphatase 2 (SHP-2) and its interaction with c-Src. Ang II-induced phosphorylation of c-Src, extracellular signal regulated kinase (ERK)1/2, and SHP-2 and activation of NAD(P)H oxidase were assessed in the absence and presence of Ang-(1-7) (10(-6) mol/L, 15 minutes) by immunoblotting and lucigenin-enhanced chemiluminescence, respectively. (D-Ala(7))-Ang I/II (1-7) (Ang fragment 1-7 receptor antagonist) was used to block Ang-(1-7) effects. Association between SHP-2 and c-Src was assessed by immunoprecipitation/immunoblotting studies. Ang II significantly increased activation of c-Src, ERK1/2, and NAD(P)H oxidase and reduced phosphorylation of SHP-2 (P<0.05) in human endothelial cells. These effects were abrogated in cells pre-exposed to Ang-(1-7). Ang fragment 1-7 receptor antagonist pretreatment blocked the negative modulatory actions of Ang-(1-7) on Ang II-induced signaling. Ang-(1-7) alone did not significantly alter phosphorylation of c-Src, ERK1/2, and SHP-2 and had no effect on basal activity of NAD(P)H oxidase. SHP-2 and c-Src were physically associated in the basal state. This association was increased by Ang-(1-7) and blocked by Ang fragment 1-7 receptor antagonist. Our findings demonstrate that, in human endothelial cells, Ang-(1-7) negatively modulates Ang II/Ang II type 1 receptor-activated c-Src and its downstream targets ERK1/2 and NAD(P)H oxidase. We also show that SHP-2-c-Src interaction is enhanced by Ang-(1-7). These phenomena may represent a protective mechanism in the endothelium whereby potentially deleterious effects of Ang II are counterregulated by Ang-(1-7).
Hypertension 2007 Dec
PMID:Angiotensin-(1-7) counterregulates angiotensin II signaling in human endothelial cells. 1798 66

Although changes in gene expression are necessary for arterial remodeling during hypertension, the genes altered and their mechanisms of regulation remain uncertain. The goal of this study was to identify cerebral artery genes altered by hypertension and define signaling pathways important in their regulation. Intact cerebral arteries from Dahl salt-sensitive normotensive and hypertensive high-salt (HS) rats were examined by immunostaining, revealing an increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and expression of the proliferative marker Ki-67 in arteries from hypertensive animals. Arterial RNA analyzed by microarray and validated with RT-quantitative PCR revealed that jun family member junB and matricellular genes plasminogen activator inhibitor-1 (PAI-1) and osteopontin (OPN) were significantly overexpressed in HS arteries. Fisher exact test and annotation-based gene subsets showed that genes upregulated by Jun and Ca(2+)/cAMP-response element-binding protein (CREB) were overrepresented. A model of cultured rat cerebrovascular smooth muscle cells was used to test the hypothesis that angiotensin II (ANG II), JunB, and CREB are important in the regulation of genes identified in the rat hypertension model. ANG II induced a transient induction of junB and a delayed induction of PAI-1 and OPN mRNA levels, which were reduced by ERK inhibition with U-0126. Silencing junB using small-interfering RNA reduced mRNA levels of OPN but not PAI-1. The silencing of CREB reduced PAI-1 induction by ANG II but enhanced the transcription of OPN. Together, these results suggest that salt-induced hypertensive disease promotes changes in matricellular genes that are stimulated by ANG II, regulated by ERK, and selectively regulated by JunB and CREB.
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PMID:Genes overexpressed in cerebral arteries following salt-induced hypertensive disease are regulated by angiotensin II, JunB, and CREB. 1815 95

G protein-coupled receptor kinase-2 and -3 (GRK2 and GRK3) in cardiac myocytes catalyze phosphorylation and desensitization of different G protein-coupled receptors through specificity controlled by their carboxyl-terminal pleckstrin homology domain. Although GRK2 has been extensively investigated, the function of cardiac GRK3 remains unknown. Thus, in this study cardiac function of GRK3 was investigated in transgenic (Tg) mice with cardiac-restricted expression of a competitive inhibitor of GRK3, i.e. the carboxyl-terminal plasma membrane targeting domain of GRK3 (GRK3ct). Cardiac myocytes from Tg-GRK3ct mice displayed significantly enhanced agonist-stimulated alpha(1)-adrenergic receptor-mediated activation of ERK1/2 versus cardiac myocytes from nontransgenic littermate control (NLC) mice consistent with inhibition of GRK3. Tg-GRK3ct mice did not display alterations of cardiac mass or left ventricular dimensions compared with NLC mice. Tail-cuff plethysmography of 3- and 9-month-old mice revealed elevated systolic blood pressure in Tg-GRK3ct mice versus control mice (3-month-old mice, 136.8 +/- 3.6 versus 118.3 +/- 4.7 mm Hg, p < 0.001), an observation confirmed by radiotelemetric recording of blood pressure of conscious, unrestrained mice. Simultaneous recording of left ventricular pressure and volume in vivo by miniaturized conductance micromanometry revealed increased systolic performance with significantly higher stroke volume and stroke work in Tg-GRK3ct mice than in NLC mice. This phenotype was corroborated in electrically paced ex vivo perfused working hearts. However, analysis of left ventricular function ex vivo as a function of increasing filling pressure disclosed significantly reduced (dP/dt)(min) and prolonged time constant of relaxation (tau) in Tg-GRK3ct hearts at elevated supraphysiological filling pressure compared with control hearts. Thus, inhibition of GRK3 apparently reduces tolerance to elevation of preload. In conclusion, inhibition of cardiac GRK3 causes hypertension because of hyperkinetic myocardium and increased cardiac output relying at least partially on cardiac myocyte alpha(1)-adrenergic receptor hyper-responsiveness. The reduced tolerance to elevation of preload may cause impaired ability to withstand pathophysiological mechanisms of heart failure.
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PMID:Cardiac-restricted expression of the carboxyl-terminal fragment of GRK3 Uncovers Distinct Functions of GRK3 in regulation of cardiac contractility and growth: GRK3 controls cardiac alpha1-adrenergic receptor responsiveness. 1816 81

The (pro)renin receptor [(P)RR] is a single trans-membrane domain receptor that mediates renin and prorenin specific effects. The receptor acts as co-factor for renin and prorenin by increasing their enzymatic activity on the cell-surface and it activates the mitogen activated protein kinases ERK1/2 cascade leading to cell proliferation and to up-regulation of profibrotic genes expression. Studies in genetically modified animals over-expressing (P)RR suggest a direct role for (P)RR cardiovascular and renal pathologies since rats over-expressing (P)RR in vascular smooth-muscle cells develop high blood pressure and those with an ubiquitous over-expression of (P)RR have glomerulosclerosis and proteinuria. A peptide called "handle region peptide" (HRP) mimicking part of the prosegment of prorenin was claimed to block prorenin binding to (P)RR and its activation. The mechanism of action of HRP and its specificity for (P)RR remains very controversial although infusion of this peptide gave spectacular results by preventing diabetic nephropathy in angiotensin II type1a receptor-deficient mice. In contrast to the other components of the renin angiotensin system, (P)RR is necessary to cell survival and proliferation and a mutation of (P)RR is associated with mental retardation and epilepsy, pointing to an essential role of (P)RR in brain development. The (pro)renin receptor is a more complex protein than anticipated and in depth studies of its functions that are likely not restricted to the renin angiotensin system are needed especially in the perspective of the design of a (P)RR blocker.
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PMID:Physiology and pharmacology of the (pro)renin receptor. 1824 93

Overexpression of the gene for heme oxygenase (HO)-1 leads to a reduction in pressor responsiveness to angiotensin II (Ang II) in experimental animals. Using rat vascular smooth muscle cells (VSMCs), we tested whether YS 49 [1-(alpha-naphtylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] inhibits Ang II-stimulated proliferation of VSMCs via induction of HO-1. YS 49 induced HO-1 protein production in a dose-and time-dependent manner in VSMCs. Treatment with YS 49 significantly and dose-dependently inhibited Ang II-induced VSMC proliferation, ROS production, and phosphorylation of JNK, but not P38 MAP kinase or ERK1/2. The antiproliferation effect of YS 49 was reversed by pretreatment with the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX), or with hemoglobin, a carbon monoxide (CO) scavenger. Similarly, VSMC proliferation, ROS production and phosphorylation of JNK by Ang II were significantly inhibited in VSMCs transfected with the HO-1 gene. Thus, HO-1 and the HO-1 product CO play, at least in part, a crucial role in Ang II-stimulated VSMC proliferation through the regulation of ROS production and JNK phosphorylation. Therefore, YS 49 has potential as a therapeutic strategy for the pathogenesis of Ang II-related vascular diseases such as hypertension and atherosclerosis, via the induction of HO-1 gene activity.
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PMID:YS 49, 1-(alpha-naphtylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, regulates angiotensin II-stimulated ROS production, JNK phosphorylation and vascular smooth muscle cell proliferation via the induction of heme oxygenase-1. 1826 5


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