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)

The effects of Welsh onion on the development of hypertension and autoxidation were studied in 6-week-old male Sprague-Dawley rats. The rats were fed with a control diet or a high-fat high-sucrose (HFS) diet with or without 5% Welsh onion (green-leafy type or white-sheath type) for 4 weeks. The systolic blood pressure was elevated and the thiobarbituric acid reactive substances (TBARS) in plasma were increased in the rats fed with the HFS diet without Welsh onion. The rats fed with the HFS diet containing Welsh onion, especially the green-leafy type, had lower blood pressure. They also had a higher level of nitric oxide (NO) metabolites in both the urine and plasma, lower activity of NADH/NADPH oxidase in the aorta, and suppressed angiotensin II production. The effect of white Welsh onion on decreasing the blood pressure was not significant, although the effects on increasing NO metabolites in the urine and decreasing NADH oxidase activity in the aorta were significant. The TBARS value in the plasma was lowered in the rats fed with either green or white Welsh onion, but the in vitro radical scavenging and ferric reducing antioxidative activities were much higher with green Welsh onion than with the white type. These results suggest that the green-leafy Welsh onion, but not the white type, reduced superoxide generation by suppressing the angiotensine II production and then the NADH/NADPH oxidase activity, increasing the NO availability in the aorta, and consequently lowering the blood pressure in the rats fed with the HFS diet. The radical scavenging and reducing antioxidative activities of green Welsh onion may also be effective in decreasing superoxide.
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PMID:Antioxidative and antihypertensive effects of Welsh onion on rats fed with a high-fat high-sucrose diet. 1604 Nov 36

Matrix metalloproteinases (MMPs), aldosterone, and reactive oxygen species (ROS) are implicated in myocardial remodeling. Although ROS, cytokines, and neurohormones regulate MMP in cardiac fibroblasts, it is unknown whether aldosterone regulates MMP in cardiomyocytes. Therefore, we tested the hypothesis that aldosterone regulates MMP in cultured adult rat ventricular myocytes (ARVMs). ARVMs were treated with aldosterone for 24 hours, and MMP-2 and MMP-9 activities were measured by zymography. Aldosterone (50 nmol/L) increased MMP-2 (43+/-5%) and MMP-9 (55+/-15%; P<0.001 for both) activities. Pretreatment with spironolactone (100 nmol/L) abolished the aldosterone-induced increase in MMP activities. Aldosterone (50 nmol/L; 30 minutes) increased mitogen/extracellular signal-regulated kinase (MEK) (31+/-3%) and extracellular signal-regulated kinase 1/2 (ERK1/2; 41+/-7%; P<0.001 for both) phosphorylation. U0126 (10 micromol/L), an MEK1/2 inhibitor, abolished the aldosterone-induced increase in MMP activities. Aldosterone increased intracellular ROS as assessed by dichlorofluorescein diacetate (27+/-4%; P<0.05). This increase was inhibited by apocynin, an NADPH oxidase inhibitor. Apocynin likewise inhibited aldosterone-induced ERK1/2 phosphorylation and the increase in MMP activities. Furthermore, the antioxidants MnTMPyP and N-acetylcysteine inhibited the aldosterone-induced increase in ERK1/2 phosphorylation and MMP activities, respectively. Protein kinase C (PKC) is implicated in the nongenomic effects of aldosterone. To test the role of PKC, ARVMs were pretreated with chelerythrine, a PKC inhibitor. Chelerythrine prevented the aldosterone-induced increase in ERK1/2 phosphorylation and MMP activities. Thus, aldosterone induces MMP activity in ARVM via activation of the mineralocorticoid receptor, PKC, and ROS-dependent activation of the MEK/ERK pathway. NADPH oxidase is a likely source of ROS in this system.
Hypertension 2005 Sep
PMID:Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. 1604 62

The association of 4 genetic polymorphisms, NAD(P)H oxidase, manganesesuperoxide dismutase (MnSOD), catalase, and endothelial nitric oxide synthase (e-NOS), was assessed with arsenic-related hypertension risk among 79 hypertensive cases and 213 controls in an arseniasis-hyperendemic area of Taiwan. Overall, MnSOD polymorphism significantly increased the risk of hypertension regardless of arsenic exposure. NADPH oxidase and eNOS polymorphisms were significantly associated with hypertension risk in the high arsenic exposure group; however, catalase polymorphism was not associated with hypertension. Groups were further stratified by triglyceride levels to evaluate whether the cumulative arsenic exposure combined the three polymorphisms together. The adjusted adds ratios (ORs) of at least two risk factors of the cumulative arsenic exposure and MnSOD, NADPH oxidase, and eNOS three-polymorphism combination versus any one risk factor of them were 0.8 (95% CI 0.3-2.3) for individuals with low triglyceride levels (<110 mg/dl) and 2.5 (95% CI 1.0-6.01) for high-triglyceride groups (>110 mg/dl), respectively. These results suggested that the NADPH oxidase, MnSOD, and e-NOS polymorphisms, but not catalase, might play a role in the development of arsenic-related hypertension, especially in subjects with high triglyceride levels.
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PMID:Genetic polymorphisms of oxidative and antioxidant enzymes and arsenic-related hypertension. 1607 60

Chronic exposure to low-O2 tension induces pulmonary arterial hypertension (PAH), which is characterized by vascular remodeling and enhanced vasoreactivity. Recent evidence suggests that reactive oxygen species (ROS) may be involved in both processes. In this study, we critically examine the role superoxide and NADPH oxidase plays in the development of chronic hypoxic PAH. Chronic hypoxia (CH; 10% O2 for 3 wk) caused a significant increase in superoxide production in intrapulmonary arteries (IPA) of wild-type (WT) mice as measured by lucigenin-enhanced chemiluminescence. The CH-induced increase in the generation of ROS was obliterated in NADPH oxidase (gp91phox) knockout (KO) mice, suggesting that NADPH oxidase was the major source of ROS. Importantly, pathological changes associated with CH-induced PAH (mean right ventricular pressure, medial wall thickening of small pulmonary arteries, and right heart hypertrophy) were completely abolished in NADPH oxidase (gp91phox) KO mice. CH potentiated vasoconstrictor responses of isolated IPAs to both 5-hydroxytryptamine (5-HT) and the thromboxane mimetic U-46619. Administration of CuZn superoxide dismutase to isolated IPA significantly reduced CH-enhanced superoxide levels and reduced the CH-enhanced vasoconstriction to 5-HT and U-46619. Additionally, CH-enhanced superoxide production and vasoconstrictor activity seen in WT IPAs were markedly reduced in IPAs isolated from NADPH oxidase (gp91phox) KO mice. These results demonstrate a pivotal role for gp91phox-dependent superoxide production in the pathogenesis of CH-induced PAH.
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PMID:Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). 1608 72

The angiotensin II type 2 (AT2) receptor is upregulated in pathological conditions such as vascular injury and exerts antagonistic effects against AT1 receptor-mediated actions. We examined the possibility that the sex difference in vascular remodeling is associated with altered AT2 receptor expression, which is located on the X chromosome. In this study, we examined this possibility by using AT2 receptor-null (Agtr2-) mice. Vascular injury was induced by polyethylene cuff placement around the femoral artery of wild-type (Agtr2+) and Agtr2- mice. In Agtr2+ mice, AT2 receptor expression in the injured artery was enhanced, and this increase was greater in female than in male mice, with no significant difference in AT1 receptor expression between male and female mice. Increases in neointimal formation, DNA synthesis, expression of monocyte chemoattractant protein-1, production of superoxide anion, and NADPH oxidase activity in the injured artery were attenuated in female compared with male mice. These parameters were augmented in Agtr2- mice, whereas the sex differences in these parameters were smaller in Agtr2- than in Agtr2+ mice. Treatment with a nonhypotensive dose of the AT1 receptor blocker valsartan decreased these parameters significantly in Agtr2+ mice, and these inhibitory effects of valsartan were greater in female mice. This sex difference in valsartan's inhibitory effect was less marked in Agtr2- mice. Our results suggest that the sex difference in response to vascular injury could be at least partially attributed to the exaggerated AT2 receptor expression in the injured vessel in female mice.
Hypertension 2005 Sep
PMID:Sex difference in vascular injury and the vasoprotective effect of valsartan are related to differential AT2 receptor expression. 1610 65

Intracellular ROS (reactive oxygen species) such as superoxide and H2O2 have been increasingly appreciated to have a role in endothelial pathophysiology. Of the several sources within the vasculature, a family of multi-subunit NADPH oxidases appears to be a predominant contributor of endothelial superoxide. More importantly, this enzyme system is activated by numerous stimuli and is involved in triggering diverse intracellular signalling pathways ('redox-sensitive' signalling pathways) that have a central role in conditions such as endothelial activation and inflammation, cell growth, apoptosis and hypertrophy. Furthermore, NADPH oxidase-derived superoxide contributes to the impairment of endothelium-dependent vasodilatation by inactivating nitric oxide; the resultant endothelial dysfunction is implicated in the pathophysiology of diseases such as atherosclerosis, hypertension, diabetic vasculopathy and heart failure. A detailed understanding of the regulation of NADPH oxidases and their modulation and downstream effects may define novel therapeutic targets for cardiovascular disease prevention and treatment in the clinical setting, in contrast with global antioxidant therapy which has to date been disappointing.
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PMID:NADPH oxidase and endothelial cell function. 1610 42

Increased vascular production of reactive oxygen species, especially superoxide anion, significantly contributes to the oxidative stress associated with hypertension. An enhanced superoxide production causes an increased inactivation of nitric oxide that diminishes nitric oxide bioavailability, thus contributing to endothelial dysfunction and hypertrophy of vascular cells. It has been shown that NADPH oxidases play a major role as the most important sources of superoxide anion in phagocytic and vascular cells. Several experimental observations have described an enhanced superoxide generation as a result of NADPH oxidase activation in hypertension. Although these enzymes respond to stimuli such as vasoactive factors, growth factors, and cytokines, recent data suggest a significant role of the genetic background in the modulation of the expression of its different components. Several polymorphisms have been identified in the promoter and in the coding region of CYBA, the gene that encodes the essential subunit of the NADPH oxidase p22phox, some of which seem to influence significantly the activity of these enzymes in the context of cardiovascular diseases. Among CYBA polymorphisms, genetic investigations have provided a novel marker, the -930(A/G) polymorphism, which determines the genetic susceptibility of hypertensive patients to oxidative stress.
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PMID:NADPH oxidase-mediated oxidative stress: genetic studies of the p22(phox) gene in hypertension. 1611 38

Aldosterone plays an important role in the pathogenesis of hypertension. We previously demonstrated that nongenomic signaling by aldosterone in vascular smooth muscle cells occurs through c-Src-dependent pathways. Here we tested the hypothesis that upregulation of c-Src by aldosterone plays a role in increased mitogen-activated protein (MAP) kinase activation, [3H]-proline incorporation, and NADPH-driven generation of reactive oxygen species, thereby inducing cell growth, collagen production, and inflammation, respectively, in vascular smooth muscle cells from spontaneously hypertensive rats. The time course of c-Src phosphorylation by aldosterone was shifted to the left in vascular myocytes from hypertensive animals. Aldosterone rapidly increased phosphorylation of p38 MAP kinase and extracellular signal-regulated kinase with significantly greater effects in cells from spontaneously hypertensive rats versus control cells (P<0.05). Aldosterone increased NADPH oxidase activity with significantly greater responses in vascular smooth muscle cells from hypertensive animals (P<0.05). These events were associated with enhanced [3H]proline incorporation (index of collagen synthesis) in cells from spontaneously hypertensive rats (P<0.05). The NADPH oxidase activity increase, collagen synthesis, c-Src, and MAP kinase phosphorylation induced by aldosterone were significantly reduced by eplerenone (selective mineralocorticoid receptor blocker) and PP2 (selective c-Src inhibitor). In conclusion, nongenomic signaling by exogenous aldosterone, mediated through c-Src, is increased in vascular smooth muscle cells from spontaneously hypertensive rats. Upregulation of c-Src signaling may be important in the profibrotic and proinflammatory actions of aldosterone in this genetic model of hypertension.
Hypertension 2005 Oct
PMID:c-Src-dependent nongenomic signaling responses to aldosterone are increased in vascular myocytes from spontaneously hypertensive rats. 1615 90

There is growing evidence that oxidative stress contributes to hypertension. Oxidative stress can precede the development of hypertension. In almost all models of hypertension, there is oxidative stress that, if corrected, lowers BP, whereas creation of oxidative stress in normal animals can cause hypertension. There is overexpression of the p22(phox) and Nox-1 components of NADPH oxidase and reduced expression of extracellular superoxide dismutase (EC-SOD) in the kidneys of ANG II-infused rodents, whereas there is overexpression of p47(phox) and gp91(phox) and reduced expression of intracellular SOD with salt loading. Several mechanisms have been identified that can make oxidative stress self-sustaining. Reactive oxygen species (ROS) can enhance afferent arteriolar tone and reactivity both indirectly via potentiation of tubuloglomerular feedback and directly by microvascular mechanisms that diminish endothelium-derived relaxation factor/nitric oxide responses, generate a cyclooxygenase-2-dependent endothelial-derived contracting factor that activates thromboxane-prostanoid receptors, and enhance vascular smooth muscle cells reactivity. ROS can diminish the efficiency with which the kidney uses O(2) for Na(+) transport and thereby diminish the P(O(2)) within the kidney cortex. This may place a break on further ROS generation yet could further enhance vasculopathy and hypertension. There is a tight relationship between oxidative stress in the kidney and the development and maintenance of hypertension.
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PMID:Oxidative stress and nitric oxide deficiency in the kidney: a critical link to hypertension? 1618 28

Superoxide anion (O2-*) production is elevated in sympathetic ganglion neurons and in the vasculature of hypertensive animals; however, it is not known what enzymatic pathway(s) are responsible for O2-* production. To determine the pathway(s) of O2-* production in sympathetic neurons, we examined the presence of mRNA of NADPH oxidase subunits in sympathetic ganglionic neurons and differentiated PC-12 cells. The mRNAs for NADPH oxidase subunits p47phox, p22phox, gp91phox, and NOX1 were present in sympathetic neurons and PC-12 cells, whereas the NOX4 homologue was present in sympathetic neurons but not PC-12 cells. Freshly dissociated celiac ganglion neurons from normal rats and PC-12 cells produced O2-* when treated with the PKC activator PMA; O2-* production increased by 317% and 254%, respectively. The PMA-evoked increases were reduced by pretreatment with the NADPH oxidase inhibitor apocynin. These findings indicate that NADPH oxidase is the primary source of O2-* in sympathetic ganglion neurons. When celiac ganglia from hypertensive rats were incubated with apocynin, O2-* levels were reduced to the same levels as normotensive animals, indicating that NADPH oxidase activity accounted for the elevated O2-* levels in hypertensive animals. To test this latter finding, we compared NADPH oxidase activity in extracts of prevertebral sympathetic ganglia of DOCA-salt hypertensive rats and sham-operated rats. NADPH oxidase activities were 49.9% and 78.6% higher in sympathetic ganglia of DOCA rats compared with normotensive controls when using beta-NADH and beta-NADPH as substrates, respectively. Thus elevated O2-* levels in hypertension may be a result of the increased activity of NADPH oxidase in postganglionic sympathetic neurons.
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PMID:Superoxide anion is elevated in sympathetic neurons in DOCA-salt hypertension via activation of NADPH oxidase. 1621 37


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