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)

Phagocytes generate superoxide anion (O(2)(-)) by a classic, 5-component NADPH oxidase. O(2)(-) contributes to hypertension in spontaneously hypertensive rats (SHR). Therefore, we tested the hypothesis that NADPH oxidase expression is enhanced in the SHR kidney. We also analyzed the localization of NADPH oxidase components in SHR kidney. Renal NADPH oxidase was quantified by reverse transcription-polymerase chain reaction and Western blotting and was localized in SHR and Wistar Kyoto rat (WKY) kidney by immunohistochemistry. The mRNA for 5 subunits of phagocyte NADPH oxidase, and also for MOX1 and RENOX (NOX4), was detected in adult rat kidney. Kidneys of adult (10 weeks old) SHR had a significantly (P<0.01) greater mRNA for p47phox (SHR 0.81 +/- 0.05 versus WKY 0.37 +/- 0.01, arbitrary unit), which was confirmed by Western blotting (SHR 0.58 +/- 0.04 versus WKY 0.42 +/- 0.04, arbitrary unit; P<0.05) and by immunohistochemistry. This higher p47phox protein expression was also detected in young prehypertensive SHR (SHR 0.61 +/- 0.05 versus WKY 0.39 +/- 0.04, arbitrary unit; P<0.01). The 10-week-old SHR contained more modest but significantly (P<0.05) greater protein for p67phox (SHR 0.54 +/- 0.02 versus WKY 0.46 +/- 0.02). Immunostaining localized p47phox, p67phox, and p22phox in vasculature, macula densa, distal convoluted tubule, cortical collecting duct, and outer and inner medullary collecting ducts. The kidney of SHR expresses genes for all the main components of phagocyte NADPH oxidase, RENOX, and MOX1. There is a prominent increase in the SHR kidney of the mRNA, and protein expression of p47phox in the vasculature, macula densa, and distal nephron, which precedes development of hypertension.
Hypertension 2002 Feb
PMID:Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney. 1184 96

Reactive oxygen species have an important pathogenic role in organ damage. We investigated the role of oxidative stress via nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase in the kidney of the Dahl salt-sensitive (DS) rats with heart failure (DSHF). Eleven-week-old DS rats fed an 8%-NaCl diet received either vehicle or imidapril (1 mg/kg per day) for 7 weeks. The renal expression of the NAD(P)H oxidase p47phox and endothelial NO synthase were evaluated. In DSHF rats, associated with increased renal angiotensin II, mRNA and protein expression of NAD(P)H oxidase p47phox were enhanced with an increase in renal lipid peroxidation production (0.33+/-0.03 versus 0.22+/-0.01 nmol/mg protein, P<0.05) and urinary excretion of hydrogen peroxide (26.9+/-6.6 versus 9.5+/-2.1 U/mg creatinine, P<0.01) compared with levels in Dahl salt-resistant rats. The endothelial NO synthase expression was decreased in the kidney. Treatment with imidapril reduced renal angiotensin II and NAD(P)H oxidase expression and the oxidative products (kidney lipid peroxidation product: 0.16+/-0.02, P<0.001; urinary hydrogen peroxide: 3.1+/-0.2, P<0.01 versus DSHF rats). Imidapril significantly decreased albuminuria and reduced glomerulosclerosis without changes in the blood pressure. In conclusion, DSHF rats showed increased oxidative stress in the kidney via NAD(P)H oxidase. Blockade of local angiotensin II with subpressor dose of imidapril inhibited NAD(P)H oxidase and prevented renal damage.
Hypertension 2002 Dec
PMID:Angiotensin II and oxidative stress in Dahl Salt-sensitive rat with heart failure. 1246 66

Mechanical stretch is a hallmark of arterial hypertension and leads to vessel wall remodeling, which involves matrix metalloproteinases (MMPs). Because mechanical stretch is further capable of inducing reactive oxygen species (ROS) formation via the NAD(P)H oxidase, we assessed whether mechanical stretch enhances MMP expression and activity in a NAD(P)H oxidase-dependent manner. Therefore, vascular smooth muscle cells (VSMCs) isolated from C57BL/6 mice were exposed to cyclic mechanical stretch. The impact of ROS was assessed using VSMCs isolated from p47phox-/- mice, deficient for a NAD(P)H oxidase subunit responsible for ROS formation. Transcript levels were investigated by cDNA array and confirmed by RT-PCR. ROS formation was determined by DCF fluoroscopy and MMP-2 activity by zymography. Mechanical stretch of wild-type VSMCs resulted in a rapid ROS formation and p47phox membrane translocation that is followed by an increase in Nox-1 transcripts. ROS formation was completely abrogated in p47phox-/- VSMCs. cDNA array further revealed an increase of MMP-2 mRNA in response to mechanical stretch, which was validated by RT-PCR. Using p47phox-/- VSMCs, this increase in MMP-2 mRNA was completely blunted. mRNA expression of tissue inhibitor of MMP-2 TIMP-1 and TIMP-2 and membrane-type 1 MMP was unaffected by mechanical stretch. Gelatinolytic activity of pro-MMP-2 has been increased rapidly in wild-type VSMCs and was completely abolished in p47phox-/- VSMCs. These results indicate that mechanical stretch induces ROS formation via the NAD(P)H oxidase and thereby enhances MMP-2 mRNA expression and pro-MMP-2 release. These results are consistent with the notion that in arterial hypertension, reactive oxygen species are involved in vascular remodeling via MMP activation. The full text of this article is available online at http://www.circresaha.org.
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PMID:Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via NAD(P)H oxidase-derived reactive oxygen species. 1275 Mar 13

Enhanced tissue angiotensin (Ang) II levels have been reported in diabetes and might lead to cardiac dysfunction through oxidative stress. This study examined the effect of blocking the Ang II type 1 (AT1) receptor on high glucose-induced cardiac contractile dysfunction. Rat ventricular myocytes were maintained in normal- (NG, 5.5 mmol/L) or high- (HG, 25.5 mmol/L) glucose medium for 24 hours. Mechanical and intracellular Ca2+ properties were assessed as peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR90), maximal velocity of shortening/relengthening (+/-dL/dt), and intracellular Ca2+ decay (tau). HG myocytes exhibited normal PS; decreased +/-dL/dt; and prolonged TPS, TR90, and tau. Interestingly, the HG-induced abnormalities were prevented with the AT1 blocker L-158,809 (10 to 1000 nmol/L) but not the Janus kinase-2 (JAK2) inhibitor AG-490 (10 to 100 micromol/L). The only effect of AT1 blockade on NG myocytes was enhanced PS at 1000 nmol/L. AT1 antagonist-elicited cardiac protection against HG was nullified by the NADPH oxidase activator sodium dodecyl sulfate (80 micromol/L) and mimicked by the NADPH oxidase inhibitors diphenyleneiodonium (10 micromol/L) or apocynin (100 micromol/L). Western blot analysis confirmed that the protein abundance of NADPH oxidase subunit p47phox and the AT1 but not the AT2 receptor was enhanced in HG myocytes. In addition, the HG-induced increase of p47phox was prevented by L-158,809. Enhanced reactive oxygen species production observed in HG myocytes was prevented by AT1 blockade or NADPH oxidase inhibition. Collectively, our data suggest that local Ang II, acting via AT1 receptor-mediated NADPH oxidase activation, is involved in hyperglycemia-induced cardiomyocyte dysfunction, which might play a role in diabetic cardiomyopathy.
Hypertension 2003 Aug
PMID:AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase. 1284 13

Renal artery stenosis (RAS) may lead to renal injury, partly mediated through increased oxidative stress. However, the potential effects of chronic oral antioxidant intervention on the stenotic kidney remain unknown. This study was designed to test the hypothesis that chronic antioxidant vitamin supplementation in RAS would preserve renal function and structure. Single-kidney hemodynamics and function were quantified in vivo in pigs using electron-beam CT after 12 weeks of unilateral RAS (n=7), a similar degree of RAS orally supplemented with vitamins C (1 g) and E (100 IU/kg) (RAS+Vitamins, n=7), or controls (normal, n=7). Renal tissue was studied ex vivo using Western blotting and immunohistochemistry. Mean arterial pressure was similarly elevated in both RAS groups, while ischemic renal volume and glomerular filtration rate were similarly reduced. Renal blood flow was decreased in RAS compared with normal (326.5+/-99.9 versus 553.4+/-48.7 mL/min, respectively, P=0.01), but preserved in RAS+Vitamins (485.2+/-104.1 mL/min, P=0.3 versus normal). The marked increase in the expression of the NADPH-oxidase subunits p47phox and p67phox, nitrotyrosine, endothelial and inducible nitric oxide synthase, and nuclear factor-kappaB observed in RAS (P<0.05 versus normal) was normalized in RAS+Vitamins (P>0.1). Furthermore, trichrome staining and the expression of transforming growth factor-beta and tissue inhibitor of matrix-metalloproteinase-1 were also decreased in RAS+Vitamins. In conclusion, chronic blockade of the oxidative stress pathway in RAS using antioxidant vitamins improved renal hemodynamics and decreased oxidative stress, inflammation, and fibrosis in the ischemic kidney. These observations underscore the involvement of oxidative stress in renal injury in RAS and support a role for antioxidant vitamins in preserving the ischemic kidney.
Hypertension 2003 Oct
PMID:Beneficial effects of antioxidant vitamins on the stenotic kidney. 1292 65

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

Vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species play critical roles in early atherogenesis, and nitric oxide (NO) is an important regulator of the cardiovascular system. Although celiprolol, a specific beta1-antagonist with weak beta2-agonistic action, stimulates endothelial nitric oxide synthase (eNOS) production, the mechanisms remain to be determined. Because it was recently reported that phosphatidylinositol 3-kinase (PI3K) and its downstream effector Akt are implicated in the activation of eNOS and that regulation of VCAM-1 expression is mediated via nuclear factor-kappaB (NF-kappaB), we hypothesized that celiprolol activates phosphorylation of eNOS through the PI3K-Akt signaling pathway; that celiprolol modulates VCAM-1 expression, which is associated with inhibiting NF-kappaB phosphorylation; and that celiprolol suppresses NAD(P)H oxidase p22phox, p47phox, gp91phox, and nox1 expression in the left ventricle of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. eNOS and Akt phosphorylation upregulated by celiprolol alone were suppressed by treatment with celiprolol plus wortmannin. Increased expression of VCAM-1, p22phox, p47phox, gp91phox, nox1, activated p65 NF-kappaB, c-Src, p44/p42 extracellular signal-regulated kinases, and their downstream effector p90 ribosomal S6 kinase phosphorylation in DOCA rats was inhibited by celiprolol. Celiprolol administration resulted in a significant improvement in cardiovascular remodeling and suppression of transforming growth factor-beta1 gene expression. In conclusion, celiprolol suppresses VCAM-1 expression because of inhibition of oxidative stress, NF-kappaB, and signal transduction, while increasing eNOS via stimulation of the PI3K-Akt signaling pathway and improving cardiovascular remodeling.
Hypertension 2003 Nov
PMID:Celiprolol activates eNOS through the PI3K-Akt pathway and inhibits VCAM-1 Via NF-kappaB induced by oxidative stress. 1455 79

The objective of this study was to determine the effect of pioglitazone on blood pressure (BP) and oxidative balance in obese, hypertensive, Sprague-Dawley rats and to identify some of the molecular mechanisms involved. After 12 weeks of a moderately high-fat diet, rats diverged into obesity-prone (OP) and obesity-resistant (OR) groups (n=6 per group). At the end of the diet, peroxisome proliferator activated receptor-gamma (PPARgamma) mRNA expression and activity in the renal cortex and medulla of OP rats were significantly lower compared with that in OR rats. Pioglitazone treatment increased PPARgamma expression and activity in OP rats, suggesting a possible direct ligand-related effect of pioglitazone. As opposed to the untreated OP group, which showed moderate hypertension (systolic BP=159+/-5.3 mm Hg) after 12 weeks, pioglitazone-treated rats were normotensive (systolic BP=123.9+/-2.7 mm Hg). Insulin production was reduced by 2-fold in the OP group treated with pioglitazone. Urinary isoprostanes and renal lipid peroxides were also reduced in OP rats treated with pioglitazone compared with untreated counterparts. Also, expression of p47phox and gp91phox, both increased in OP versus OR rats, was reduced in the former by pioglitazone treatment. In addition, pioglitazone treatment increased nitrate/nitrite excretion and expression of renal endothelial and neuronal nitric oxide synthase. Collectively, the results show that pioglitazone treatment prevented hypertension and renal oxidative stress both by reducing free-radical production and by increasing nitric oxide production/availability.
Hypertension 2004 Jan
PMID:Pioglitazone prevents hypertension and reduces oxidative stress in diet-induced obesity. 1463 18

The involvement of oxidative stress in polymorphonuclear leukocytes (PMN) in the pathogenesis of hypertension remains to be elucidated. We analyzed the generation of reactive oxygen species (ROS) by the circulating and peritoneally infiltrating PMN from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Flow cytometric analysis revealed that ROS generation by PMN from SHR was higher than that from WKY before (at 6 weeks of age) and after (at 16 weeks of age) the onset of hypertension. In vivo, ROS generation by PMN from SHR, but not that by PMN from WKY, was significantly suppressed by 10-week treatment with 50 mg/kg/day carvedilol, and this treatment did not affect blood pressure. Western blotting analysis revealed that protein kinase C alpha (PKCalpha), but not PKCbetaI or betaII, was activated more strongly in PMN from SHR than in PMN from WKY. Furthermore, expression of p47phox of nicotinamide adenine dinucleotide phosphate oxidase, but not of p67phox, in PMN from SHR was higher than that in PMN from WKY. These results suggest that ROS generation by PMN is principally enhanced in SHR through activation of PKCalpha and p47phox.
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PMID:Activation of protein kinase C and nicotinamide adenine dinucleotide phosphate oxidase in leukocytes of spontaneously hypertensive rats. 1471 43

We investigated the effects of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) on the inhibitory effects of an angiotensin II type-1 receptor (AT1) blocker on atherosclerosis and explored cellular mechanisms. We gave apolipoprotein E null mice a high-cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition. Neither 1 mg/kg per day of valsartan nor 3 mg/kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration; however, both drugs decreased plaque area and lipid deposition after 10 weeks. We then reduced the doses of both drugs to 0.1 mg/kg per day and 1 mg/kg per day, respectively. At these doses, neither drug had an effect on atherosclerotic lesions. When both drugs were combined at these doses, a significant reduction in atherosclerotic lesions was observed. Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide phosphate oxidase subunits p22phox and p47phox, production of superoxide anion, the expression of monocyte chemoattractant protein-1, and intercellular adhesion molecule-1 expression were observed. These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade, particularly when given concomitantly, blunts oxidative stress and inflammation independent of blood pressure or cholesterol-related effects.
Hypertension 2004 Nov
PMID:Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker, valsartan, on atherosclerosis. 1545 25


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