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)

Cadmium (Cd) is frequently used in various industrial applications and is a ubiquitous environmental toxicant, also present in tobacco smoke. An important route of exposure is the circulatory system whereas blood vessels are considered to be main stream organs of Cd toxicity. Our previous results indicate that cadmium chloride (CdCl2) affects mean arterial blood pressure in hypertensive rats. We hypothesized that Cd alters the intracellular calcium transient mechanism, by cadmium-induced stimulation of MAPKs (ERK 1 & 2) which is mediated partially through calcium-dependent PKC mechanism. To investigate this hypothesis, we exposed primary cultures of vascular smooth muscle cells (VSMCs) from wistar kyoto (WKY) and spontaneously hypertensive rats (SHR) to increased concentrations of CdCl2 on cell viability, expression of mitogen-activated protein kinases (MAPKs/ERK 1 & 2), and protein kinase C (PKC) which are activated by Cd in several cell types. The results from these studies indicate that CdCl2 decreased cell viability of both SHR and WKY VSMCs in a concentration dependent-manner. Viability of both cell types decreased 33+/-5.3 (SHR) and 39+/-2.3% (WKY) when exposed to 1 microM CdCl2, whereas, 8 and 16 microM reduced viability by 66+/-3.1 and 62+/-4.5% in SHR cells. CdCl2 increased ERK 1 & 2 in a biphasic manner with maximum increase occurring when cells are exposed to 1 and 4 muM in SHR VSMCs, whereas, a reduction in ERK 1 and 2 is observed when WKY cells are treated with 2 microM. The results also indicate that CdCl2 increased PKC a/Beta in both SHR and WKY VSMCs with a greater increase in expression in SHR VSMCs. In addition, the [Ca2+]i chelator, BAPTA, suppressed the CdCl2 effect, whereas, the PKC inhibitor, GF109203X, reduced the CdCl2 induced-effect on PKC expression. The present studies support the hypothesis that Cd can be a risk factor of hypertension through dysfunction of vascular smooth muscle cells under certain conditions.
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PMID:Cadmium toxicity on arterioles vascular smooth muscle cells of spontaneously hypertensive rats. 1715 73

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

Insulin (Ins) and angiotensin II (AII) play pivotal roles in the control of two vital and closely related systems: the metabolic and the circulatory, respectively. A failure in the proper action of each of these hormones results, to a variable degree, in the development of two highly prevalent and commonly overlapping diseases--diabetes mellitus (DM) and hypertension (AH). In recent years, a series of studies has revealed a tight connection between the signal transduction pathways that mediate Ins and AII actions in target tissues. This molecular cross-talk occurs at multiple levels and plays an important role in phenomena that range from the action of anti-hypertensive drugs to cardiac hypertrophy and energy acquisition by the heart. At the extracellular level, the angiotensin-converting enzyme controls AII synthesis but also interferes with Ins signaling through the proper regulation of AII and the accumulation of bradykinin. At an early intracellular level, AII, acting through JAK-2/IRS-1/PI3-kinase, JNK and ERK, may induce the serine phosphorylation and inhibition of key elements of the Ins-signaling pathway. Finally, by inducing the expression of the regulatory protein SOCS-3, AII may impose a late control on the Ins signal. This review will focus on the main advances obtained in this field and will discuss the implications of this molecular cross-talk in the common clinical association between DM and AH.
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PMID:[Insulin and angiotensin II signaling pathways cross-talk: implications with the association between diabetes mellitus, arterial hypertension and cardiovascular disease]. 1750 26

Experimental and clinical evidence indicates that Endogenous Ouabain (EO) and Adducin polymorphism play a pathogenetic role in hypertension and related organ complications. These effects occur through a complex interaction of genetic molecular mechanisms regulating renal sodium reabsorption and vascular function. The activation of a Na-K ATPase-Src-EGFr-ERK signaling pathway within the restricted membrane subdomains of caveolae by Ouabain has been associated to hypertension and cardiac remodeling. Rostafuroxin (PST 2238) is a novel anti-hypertensive compound able to selectively antagonize EO/Ouabain and Adducin hypertensive effect and Ouabain-induced cardiac hypertrophy in rats. Studies have been conducted in vivo and in a cell-free system to prove that Rostafuroxin exerts its antihypertensive and antihypertrophic effects by antagonizing the Src-dependent signaling triggered by Ouabain. At the vascular level, Rostafuroxin antagonizes the Ouabain-mediated increase of myogenic vascular tone. This peculiar and novel mechanism of action, together with a good tolerability and efficacy both in animal models and hypertensive patients, make Rostafuroxin the prototype of a new class of antihypertensive compounds able to antagonize EO/ Ouabain and Adducin molecular effects.
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PMID:Ouabain-dependent signaling in caveolae as a novel therapeutic target for hypertension. 1753 30

Almost every systemic vessel is surrounded by a layer of perivascular adipose tissue (PVAT), which had been mainly considered as a mechanical support for vasculature. However, recent advances have revealed that PVAT is an active player in controlling vessel function. PVAT releases relaxation factor(s) with unknown chemical identity (named perivascular adipocyte-derived relaxation factor, PVRF) that attenuates vasoconstriction to various agonists including phenylephrine, serotonin, angiotensin II, and U 46619 (a thromboxane A(2) mimic), through activation of K(+) channels. PVAT also promotes vasoconstriction to perivascular nerve stimulation by producing vasoconstrictor or facilitator (named perivascular adipocyte-derived constricting factor, PVCF), which includes superoxide and was mediated through activation of tyrosine kinase and MAPK/ERK pathways. Therefore, PVAT has a dual regulatory role in modulating vessel function, attenuating vasoconstriction to agonists by PVRF and promoting constriction to perivascular nerve excitation by PVCF. In vivo, normal amount of PVAT (total body fat as well) is likely to be important in maintaining the homeostasis of vascular tone and blood pressure, since lipoatrophic mice developed hypertension. On the other end, excessive accumulation of body fat (obesity) impaired PVRF production/action, despite an increase in the amount of PVAT. In spontaneously hypertensive rats, an animal model of hypertension without obesity, the ability of PVAT to attenuate vasoconstriction to agonists was reduced, and treatment with atorvastatin improved PVAT function. PVAT, vasodilating and constricting factors of PVAT origin, and signalling pathways of these factors may represent new targets for developing new strategies to treat vascular disorders associated with abnormal adiposity.
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PMID:Dual modulation of vascular function by perivascular adipose tissue and its potential correlation with adiposity/lipoatrophy-related vascular dysfunction. 1762 51

Renal cell cancer (RCC) is a relatively uncommon malignancy, with 51,190 cases expected to be diagnosed in 2007. Localized disease is curable by surgery; however, locally advanced or metastatic disease is not curable in most cases and, until recently, had a limited response to drug treatment. Historically, biologic response modifiers or immunomodulating agents were tested in clinical trials based on observations that some cases of RCC can spontaneously regress. High-dose aldesleukin is approved by the United States Food and Drug Administration as a treatment for advanced RCC; however, the drug is associated with a high frequency of severe adverse effects. Responses have been observed with low-dose aldesleukin and interferon alfa, but with little effect on overall survival. Sorafenib and sunitinib are novel therapies that target growth factor receptors known to be activated by the hypoxia-inducible factor and the Ras-Raf/MEK/ERK pathways. These pathways are important in the pathophysiology of RCC. Sorafenib and sunitinib have shown antitumor activity as first- and second-line therapy in patients with cytokine-refractory metastatic RCC who have clear-cell histology. Although complete responses are not common, both drugs promote disease stabilization and increase progression-free survival. This information suggests that disease stabilization may be an important determinant for response in RCC and possibly other cancers. Sorafenib and sunitinib are generally well tolerated and are considered first- and second-line treatment options for patients with advanced clear cell RCC. In addition, sorafenib and sunitinib have shown promising results in initial clinical trials evaluating antitumor activity in patients who are refractory to other antiangiogenic therapy. The most common toxicities with both sorafenib and sunitinib are hand-foot syndrome, rash, fatigue, hypertension, and diarrhea. Research is directed toward defining the optimal use of these new agents.
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PMID:Sorafenib and sunitinib: novel targeted therapies for renal cell cancer. 1765 13

Hibiscus sabdariffa L., a tropical beverage material and medical herb, is used commonly as in folk medicines against hypertension, pyrexia, inflammation, liver disorders, and obesity. This report was designed to investigate the inhibitory mechanisms of hibiscus extract on adipocyte differentiation in 3T3-L1 preadipocytes. The possible inhibitory pathways that regulate the adipocyte differentiation contain the adipogenic transcription factors, C/EBPalpha and PPARgamma, PI3-kinase, and MAPK pathway. In this study, we examined whether hibiscus extract affected the adipogenesis via these three pathways. To differentiate preadipocyte in adipocyte, confluent 3T3-L1 preadipocytes were treated with the hormone mixture including isobutylmethylxanthine, dexamethasone, and insulin (MDI). Hibiscus extract inhibited significantly the lipid droplet accumulation by MDI in a dose-dependent manner and attenuated dramatically the protein and mRNA expressions of adipogenic transcriptional factors, C/EBPalpha and PPARgamma, during adipogenesis. The increase of phosphorylation and expression of PI3-K/Akt during adipocytic differentiation was markedly inhibited by treatment with hibiscus extract or PI3-K inhibitors. Furthermore, the phosphorylation and expression of MEK-1/ERK known to regulate the early phase of adipogenesis were clearly decreased with the addition of hibiscus extract. Taken together, this report suggests that hibiscus extract inhibits the adipocyte differentiation through the modulation of PI3-K/Akt and ERK pathway that play pivotal roles during adipogenesis.
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PMID:Hibiscus sabdariffa L. water extract inhibits the adipocyte differentiation through the PI3-K and MAPK pathway. 1790 78

Leptin, one of the adipocyte-secreted peptides, is involved in the control of appetite and body weight. Several studies have demonstrated that plasma leptin levels are elevated in obese subjects and are positively correlated with body weight. The arterial endothelin (ET) system plays an important role in the regulation of vascular tone, and ET-1 overexpression may be involved in the pathogenesis of the hypertension associated with insulin resistance. This study was performed to explore the regulatory effects of leptin on ET receptor expression and ET binding in A10 vascular smooth muscle cells (VSMCs) by use of Northern blotting, immunoblotting, and a (125)I-labeled ET-1 binding assay. The effect of leptin on ET receptor-mediated cell proliferation was also tested. The results showed that leptin caused a significant increase in [(125)I]-ET-1 binding, which was time- and dose-dependent. Immunoblotting showed that expression of the ET type A receptor (ET(A)R) in leptin (10(-7) M)-treated cells was increased by up to 2.3-fold compared with controls. Levels of ET(A)R mRNA measured by Northern blotting were also increased by up to 2.2-fold in leptin (10(-7) M)-treated cells. Pretreatment with an ERK inhibitor, PD-98059 (2.5 x 10(-5) M), blocked the leptin-induced increase in (125)I-ET-1 binding. Finally, ET-1 (10(-7) M)-stimulated cell proliferation was enhanced by leptin (10(-7) M) pretreatment, with a maximal increase of twofold compared with controls. In conclusion, leptin increases ET(A)R expression in VSMCs in a time- and dose-dependent manner. This effect is ERK dependent and is associated with increased ET-1-stimulated cell proliferation. These findings provide support for roles for leptin and the ET system in the pathogenesis of obesity-associated hypertension.
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PMID:Leptin increases endothelin type A receptor levels in vascular smooth muscle cells. 1805 87

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


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