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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The importance of reactive oxygen species (ROS) in vascular physiology and pathology is becoming increasingly evident. All cell types in the vascular wall produce ROS derived from superoxide-generating protein complexes similar to the leukocyte NADPH oxidase. Specific features of the vascular enzymes include constitutive and inducible activities, substrate specificity, and intracellular superoxide production. Most phagocyte enzyme subunits are found in vascular cells, including the catalytic gp91phox (aka, nox2), which was the earliest member of the newly discovered nox family. However, smooth muscle frequently expresses nox1 rather than gp91phox, and nox4 is additionally present in all cell types. In cell culture, agonists increase ROS production by activating multiple signals, including protein kinase C and Rac, and by upregulating oxidase subunits. The oxidases are also upregulated in vascular disease and are involved in the development of atherosclerosis and a significant part of angiotensin II-induced hypertension, possibly via nox1 and nox4. Likewise, enhanced vascular oxidase activity is associated with diabetes. Therefore, members of this enzyme family appear to be important in vascular biology and disease and constitute promising targets for future therapeutic interventions.
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PMID:Vascular NAD(P)H oxidases: specific features, expression, and regulation. 1285 11

Deoxycorticosterone acetate (DOCA)-salt hypertension is characterized by low renin/angiotensin but increased arterial superoxide levels. We have recently reported that the arterial endothelin-1 (ET-1) level is increased, resulting in NADPH oxidase activation and superoxide generation. However, the effect of ET-1 on venous superoxide production and its relation to venoconstriction are unknown. The present study tested the hypotheses that ET-1 stimulates venous NADPH oxidase and superoxide via its ET(A) receptors, resulting in enhanced venoconstriction in DOCA-salt hypertensive rats. Treatment with ET-1 (0.01 to 1 nmol/L), but not the selective ET(B) receptor agonist sarafotoxin s6c, of vena cavas of normal rats concentration-dependently increased superoxide levels, an effect that was abolished by the selective ET(A) receptor antagonist ABT-627. Although the ET-1 level was not increased in the vena cava and plasma, both venous NADPH oxidase activity and superoxide levels were significantly higher in DOCA-salt compared with sham rats. Moreover, ET-1 treatment (10(-9) mol/L, 10 minutes) of isolated vena cavas further elevated superoxide levels in DOCA-salt rats only but not sham rats, an effect that was abrogated by the superoxide scavenger tempol. Similarly, ET-1-induced contractions of isolated vena cavas of DOCA-salt but not sham rats were significantly inhibited by tempol. The NADPH oxidase inhibitor apocynin significantly reduced superoxide levels in vena cavas of DOCA-salt rats and in ET-1-treated vena cavas of normal rats. Finally, in vivo ET(A) receptor blockade by ABT-627 significantly lowered venous superoxide levels and blood pressure in DOCA-salt but not sham rats. These results suggest that superoxide contributes to ET-1-induced venoconstriction through an elevated venous NADPH oxidase activity in mineralocorticoid hypertension.
Hypertension 2003 Sep
PMID:NADPH oxidase-derived superoxide augments endothelin-1-induced venoconstriction in mineralocorticoid hypertension. 1288 92

The small G protein Rac has been implicated in multiple cardiovascular processes. Rac has two major functions: 1) it regulates the organization of the actin cytoskeleton, and 2) it controls the activity of the key enzyme complex NADPH oxidase to control superoxide production in both phagocytes and nonphagocytic cells. In phagocytes, superoxide derived from NADPH has a bactericidal function, whereas Rac-derived superoxide in the cardiovascular system has a diverse array of functions that have recently been a subject of intense interest. Rac is differentially activated by cellular receptors coupled to distinct Rac-activating adapter molecules, with each leading to pathway-specific arrays of downstream effects. Thus it may be important to investigate not just whether Rac is activated but also where, how, and for what effector. An understanding of the biochemical functions of Rac and its effectors lays the groundwork for a dissection of the exact array of effects produced by Rac in common cardiovascular processes, including cardiac and vascular hypertrophy, hypertension, leukocyte migration, platelet biology, and atherosclerosis. In addition, investigation of the spatiotemporal regulation of both Rac activation and consequent superoxide generation may produce new insights into the development of targeted antioxidant therapies for cardiovascular disease and enhance our understanding of important cardiovascular drugs, including angiotensin II antagonists and statins, that may depend on Rac modulation for their effect.
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PMID:Rac regulates cardiovascular superoxide through diverse molecular interactions: more than a binary GTP switch. 1295 25

Derangements in the production and degradation of reactive oxygen species (ROS) as well as nitric oxide (NO) have been implicated in cardiovascular diseases. We explored how supplementation with l-arginine, an NO synthase substrate, restores such derangements of ROS/NO systems in Dahl salt-sensitive, hypertensive (DS) rats. We detected an increase of NADPH oxidase activity, a key enzyme that produces superoxide, in the membrane fraction of the renal cortex derived from DS rats loaded with high salt for 4 weeks; high salt loading also remarkably increased urinary H2O2, 8-isoprostane, and thromboxane B2 excretion and decreased plasma NO end products. These changes from high salt loading were counteracted by oral l-arginine supplementation. We further examined expression patterns of NADPH oxidase subunits in renal cortex derived from these animals. High salt loading increased gp91phox and p47phox but not p22phox or Rac1 or mRNA abundance, which were counteracted with L-arginine supplementation. Western blot analyses after subcellular fractionation revealed that l-arginine supplementation distinctly decreases membrane localization of p47phox protein, as it decreases total expression of Rac1 protein in DS rats with high salt loading. These results disclose that high salt loading causes a deficiency in available L-arginine amounts for NO synthases and induces NADPH oxidase activation in the renal cortex of DS rats, which l-arginine supplementation markedly restores. Since superoxide rapidly eliminates NO, which inhibits sodium reabsorption in the cortical collecting duct, superoxide production caused by upregulated NADPH oxidase activity in the renal cortex of high salt-loaded DS rats may accelerate sodium reabsorption and hypertension.
Hypertension 2003 Nov
PMID:L-arginine reverses p47phox and gp91phox expression induced by high salt in Dahl rats. 1450 57

Although hypertension is a major risk factor for atherosclerosis, its underlying mechanisms remain to be delineated. We have recently reported that both endothelin-1 (ET-1) and vascular cellular adhesion molecule-1 (VCAM-1) levels, key early markers of atherosclerosis, are significantly elevated in carotid arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, a model known for its suppressed plasma renin levels. This study tested the hypothesis that ET-1 augments arterial VCAM-1 expression through NADPH oxidase-derived superoxide (O2-). Carotid arteries of DOCA-salt or sham-operated rats were transduced ex vivo with extracellular superoxide dismutase (EC-SOD), dominant negative HA-tagged N17Rac1 that inhibits Rac1, the small GTPase component of NADPH oxidase, or beta-galactosidase (beta-gal) reporter gene (5x10(10) plaque formation units [pfu]/mL), and the effect of transgene expression on O2- and VCAM-1 levels was assayed 24 hours afterward. The arterial activity of NADPH oxidase but not xanthine oxidase was significantly higher in DOCA-salt than in sham rats, which was abolished by the selective ETA receptor antagonist ABT-627 (3x10(-8) mol/L), NADPH oxidase inhibitor apocynin (10(-4) mol/L), or dominant negative Rac1 gene transfer. The levels of O2- and VCAM-1 were significantly increased in arteries of DOCA-salt rats, an effect that was ameliorated after EC-SOD or dominant negative Rac1 but not beta-gal reporter gene transfer. ABT-627 and apocynin also significantly reduced elevated VCAM-1 levels in ET-1-treated arteries of normal rats and arteries of DOCA-salt rats. The results of this study indicate that ET-1 stimulates arterial VCAM-1 expression by producing O2- from an ETA receptor/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.
Hypertension 2003 Nov
PMID:Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in mineralocorticoid hypertension. 1451 26

Angiotensin II is known to stimulate NADPH oxidase-dependent superoxide (O2-) generation, which may contribute to the acute renal vasoconstrictor and antinatriuretic actions of this peptide. To evaluate this hypothesis, the effects of a superoxide dismutase mimetic (tempol) or a NADPH inhibitor (apocynin) on the angiotensin renal actions were studied. Renal cortical nitric oxide (NO) was measured electrochemically in vivo. Tempol increased sodium excretion and NO levels. Apocynin raised renal blood flow, glomerular filtration rate, sodium excretion, and NO levels. These results indicate the presence of an endogenous NADPH oxidase-dependent O2- generation that may modulate renal function by scavenging NO. Angiotensin II infusion reduced renal blood flow, glomerular filtration, sodium excretion, and NO levels in a dose-dependent manner. The angiotensin receptor antagonist valsartan, tempol, or apocynin blunted the angiotensin effects on renal excretion and NO, suggesting that angiotensin receptors stimulation induces the NADPH oxidase-dependent O2- generation that might reduce NO bioavailability. This idea is supported by the finding that angiotensin increased O2- generation in renal homogenates, and this effect was prevented by valsartan, apocynin, or tempol. These results indicate that some of the acute renal effects of angiotensin II may be enhanced by an increased NADPH oxidase-derived O2- production that reduces renal NO bioavailability.
Hypertension 2003 Dec
PMID:Role of superoxide in modulating the renal effects of angiotensin II. 1459 45

Oxidative stress occurs in a tissue or in the whole body when the total oxidant production exceeds the antioxidant capacity. Recent studies in human essential hypertension indicate that free radical production is increased and antioxidant levels are decreased, and more than one-half of these hypertensives have a salt-sensitive type of hypertension with progressive renal damage. Increased oxidative stress may also play a critical role in animal models of salt-sensitive hypertension. The stroke-prone spontaneously hypertensive rats (SHRSP) exhibits salt-sensitivity, vascular release of superoxide is increased, and total plasma antioxidant capacity is decreased. The superoxide release in the SHRSP rats inactivates nitric oxide, and superoxide dismutase (SOD) administration returns the bioactive nitric oxide levels to normal. The deoxycorticosterone acetate (DOCA)-salt hypertensive rat is salt-sensitive, aortic superoxide production is increased, and renal inflammation is significant. Treatment of the DOCA-salt rats with apocynin, an NADPH oxidase inhibitor, decreased aortic superoxide production and decreased arterial pressure. The Dahl salt-sensitive (S) rat has increased mesenteric microvascular and renal superoxide production and increased plasma levels of H2O2. The renal protein expression of SOD is decreased in the kidney of Dahl S rats, and long-term administration of Tempol, a superoxide mimetic, significantly decreased arterial pressure and renal damage. In conclusion, both human hypertension and experimental models of salt-sensitive hypertension have increased superoxide release, decreased antioxidant capacity and elevated renal damage.
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PMID:Renal and vascular oxidative stress and salt-sensitivity of arterial pressure. 1461 40

Out-of-control reactive oxygen species (ROS) signaling is one of the key events in the pathogenesis of endothelial dysfunction and essential hypertension. We observed that tea polyphenols decreased the production of ROS via regulation of the protein expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in bovine carotid artery endothelial cells (BCAECs). Both green tea polyphenols (GTP) and black tea polyphenols (BTP) down-regulated the expression of NADPH oxidase subunits p22phox and p67phox while up-regulating catalase expression (p < 0.05, respectively). Pre-treatment with GTP or BTP for 24 h significantly decreased the superoxide anion level (p < 0.05) and permeable fluorescence intensities in Ang II-stimulated BCAECs. A decrease in cell permeability was also observed by pre-treatment with diphenylene iodonium chloride (DPI) or vitamin E (p < 0.05, respectively). The result demonstrates that tea polyphenols alleviate angiotensin (Ang) II-induced hyperpermeability mainly by decreasing ROS production. Our results suggest that tea polyphenols regulate ROS-related protein expression and may be beneficial in preventing endothelial cell dysfunction and development of cardiovascular diseases, including hypertension.
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PMID:Tea polyphenols regulate nicotinamide adenine dinucleotide phosphate oxidase subunit expression and ameliorate angiotensin II-induced hyperpermeability in endothelial cells. 1462 Nov 86

Resveratrol is a phytoestrogen naturally found in grapes and is among the major constituents of wine thought to have a cardioprotective effect. Endothelin-1 (ET-1) is a potent vasopressor synthesized by endothelial cells both in culture and in vivo. The aims of this study were to test the hypothesis that resveratrol may alter strain-induced ET-1 gene expression and to identify the putative underlying signaling pathways in endothelial cells. We show that resveratrol indeed potently inhibits strain-induced ET-1 secretion, ET-1 mRNA level, and ET-1 promoter activity. Resveratrol also inhibits strain-increased NADPH oxidase activity, reactive oxygen species formation, and extracellular signal-regulated kinases1/2 (ERK1/2) phosphorylation. Furthermore, pretreating cells with resveratrol or antioxidant N-acetyl-cysteine decreases strain-increased or hydrogen peroxide-increased ET-1 secretion, ET-1 promoter activity, and ET-1 mRNA and ERK1/2 phosphorylation. Using both the electrophoretic mobility shift assay and a reporter gene assay, resveratrol and N-acetyl-cysteine also attenuated the strain-stimulated activator protein-1 binding activity and activator protein-1 reporter activity. In summary, we demonstrate for the first time that resveratrol inhibits strain-induced ET-1 gene expression, partially by interfering with the ERK1/2 pathway through attenuation of reactive oxygen species formation. Thus, this study provides important new insights in the molecular pathways that may contribute to the proposed beneficial effects of resveratrol in the cardiovascular system.
Hypertension 2003 Dec
PMID:Inhibition of cyclic strain-induced endothelin-1 gene expression by resveratrol. 1462 29

1. Vascular cells have evolved to use reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, as signalling molecules. Under physiological conditions, ROS are important regulators of cell cycle, protein kinase activity and gene expression. However, in vascular disease states, such as hypertension and hypercholesterolaemia, excessive production of ROS may overwhelm the anti-oxidant defence mechanisms of cells, resulting in 'oxidative stress', damage to the artery wall and, ultimately, development of atherosclerotic plaques. 2. The primary source of ROS in the vasculature is NADPH oxidase. There appear to be at least three isoforms of NADPH oxidase expressed in the vascular wall, each differing with respect to the flavin-containing catalytic subunit it uses to transfer electrons from NADPH to molecular oxygen. Thus, although endothelial cells and adventitial fibroblasts express a gp91phox-containing NADPH oxidase similar to that originally identified in phagocytes, vascular smooth muscle cells may rely on novel homologues of gp91phox, namely Nox1 and Nox4, to produce superoxide. 3. Controversy remains over which isoform(s) of NADPH oxidase is responsible for the oxidative stress associated with vascular diseases. We and others have shown that although gp91phox mRNA expression is upregulated during atherogenesis in human and animal models, expression of the Nox4 subunit remains unchanged. Nox1 expression is also likely to be increased in diseased arteries; however, its relative level of expression, at least at the mRNA level, appears to be markedly lower than that of the other gp91phox homologues, even after upregulation. 4. Whether these findings suggest that a gp91phox-containing NADPH oxidase is more important than either Nox4 or Nox1 in vascular disease awaits studies examining relative protein expression and enzyme kinetics of each subunit, as well as the effects of targeted gene deletion of each of these gp91phox homologues on atherogenesis.
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PMID:Novel isoforms of NADPH oxidase in vascular physiology and pathophysiology. 1467 49


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