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)

Superoxide anion (O2-) plays a key role in the endogenous suppression of endothelium-derived nitric oxide (NO) bioactivity and has been implicated in the development of hypertension. In previous studies, we found that O2- is produced predominantly in the adventitia of isolated rabbit aorta and acts as a barrier to NO. In the present studies, we characterize the enzyme responsible for O2- production in the adventitia and show that this enzyme is a constitutively active NADPH oxidase with similar composition as the phagocyte NADPH oxidase. Constitutive O2--generating activity was localized to aortic adventitial fibroblasts and was enhanced by the potent vasoconstrictor angiotensin II. Immunohistochemistry of aortic sections demonstrated the presence of p22(phox), gp91(phox), p47(phox), and p67(phox) localized exclusively in rabbit aortic adventitia, coincident with the site of staining for O2- production. Furthermore, immunodepletion of p67(phox) from adventitial fibroblast particulates resulted in the loss of NADPH oxidase activity, which could be restored by the addition of recombinant p67(phox). Further study into the regulation of this adventitial source of O2- is important in elucidating the mechanisms regulating the bioactivity of NO and may contribute to our understanding of the pathogenesis of hypertension.
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PMID:Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement by angiotensin II. 940 39

A heme-binding protein with a molecular mass of 22 kDa, termed p22 HBP, was purified from mouse liver cytosol, using blue Sepharose CL-6B. We identified a cDNA encoding p22 HBP, and sequence analysis revealed that p22 HBP comprises 190 amino acid residues (Mr 21,063) and has no homology to any other known heme-binding protein. The p22 HBP mRNA (approximately 1.0 kilobases) is ubiquitously expressed in various tissues and is extremely abundant in the liver. cDNA allows for expression of active p22 HBP, with a high affinity for 55Fe-hemin, with a Kd of 26 +/-1.8 nM. The Bmax of hemin binding to p22 HBP was 0.55 +/- 0.021 mol/mol of protein, a value consistent with one heme molecule binding per molecule of protein. The order of potency of different ligands to compete against 55Fe-hemin binding to p22 HBP was hemin = protoporphyrin IX > coproporphyrin III > bilirubin > palmitic acid > all-trans-retinoic acid. Treatment of mouse erythroleukemia (MEL) cells with dimethyl sulfoxide or hemin resulted in an increase in p22 HBP mRNA. The immunoblot analysis showed that p22 HBP increased with time in dimethyl sulfoxide- and hemin-induced MEL cells. Conversely, transfer of antisense oligonucleotides to p22 HBP cDNA resulted in a decrease of p22 HBP in dimethyl sulfoxide-treated MEL cells, and the heme content in these cells decreased to 66-71% of sense oligonucleotides-transferred cells. Thus, this newly identified heme-binding protein, p22 HBP, may be involved in heme utilization for hemoprotein synthesis and even be coupled to hemoglobin synthesis during erythroid differentiation.
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PMID:Molecular characterization of a newly identified heme-binding protein induced during differentiation of urine erythroleukemia cells. 981 49

Turner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.
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PMID:Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1. 983 29

-Recent reports suggest that the increased production of reactive oxygen species (ROS) in the vascular wall may contribute to the functional and structural changes associated with hypertension and atherosclerosis. Although glucocorticoid therapy can promote atherosclerosis, protective effects of these compounds on vascular lesion formation have been reported. In the present study, we investigated whether ROS production in cultured human aortic smooth muscle cells (HSMCs) can be modulated by glucocorticoids. Pretreatment of HSMCs with dexamethasone for 24 hours attenuated the basal and platelet-derived growth factor (PDGF)-AB- and angiotensin II-induced superoxide anion (O2. -) production. PDGF-AB-stimulated O2. - production was also inhibited by prednisolone and hydrocortisone but not by other steroids, such as testosterone and norgestrel. Incubation of HSMCs with glucocorticoids for 24 hours decreased 2',7'-dichlorodihydrofluorescein (DCHF) oxidation, an indicator of intracellular ROS levels. Dexamethasone decreased the mRNA expression of p22 phox, one of the components of NADPH oxidase, but had no effect on the activity of superoxide dismutase. The effects of dexamethasone on DCHF oxidation, and p22 phox mRNA expression and PDGF-AB-stimulated O2. - production were inhibited by the glucocorticoid receptor antagonist RU486. These results indicate that glucocorticoids decrease O2. - production by HSMCs via a receptor-dependent pathway. This effect is likely to be mediated by a decrease in the generating system, such as downregulation of p22 phox mRNA, rather than an increased inactivation of O2. -. The inhibition of ROS production might contribute to the local protective effects that glucocorticoids have on vascular lesion formation.
Hypertension 1998 Dec
PMID:Glucocorticoids inhibit superoxide anion production and p22 phox mRNA expression in human aortic smooth muscle cells. 985 78

In the domestic chicken, Gallus gallus, the retina and pineal gland contain circadian clocks that are directly entrained by environmental light-dark cycles. To identify novel genes that are expressed in the retina and pineal gland, we performed two-tissue suppression subtractive hybridization (SSH). Two-tissue SSH is designed to identify genes expressed in common between two RNA samples while at the same time subtracting out abundant transcripts. Using this method, we identified a novel chicken gene, named ckSoul, that is strongly expressed in the retina and pineal gland. The protein product of ckSoul is similar to a novel heme-binding protein (p22 HBP) and to an uncharacterized mammalian gene in the expressed sequence tag (EST) database. The mouse transcript of this new gene is expressed in the retina and may represent the mammalian ortholog of ckSoul. Molecular analysis of the mammalian and chicken proteins suggests SOUL and HBP are members of a new family of heme-binding proteins.
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PMID:Discovery of a putative heme-binding protein family (SOUL/HBP) by two-tissue suppression subtractive hybridization and database searches. 1064 Jun 88

Increased vascular reactive oxygen species production, especially superoxide anion, contributes significantly in the functional and structural alterations present in hypertension. An enhanced superoxide production causes a diminished NO bioavailability by an oxidative reaction that inactivates NO. Exaggerated superoxide levels and a low NO bioavailability lead to endothelial dysfunction and hypertrophy of vascular cells. It has been shown that the enzyme NAD(P)H oxidase plays a major role as the most important source of superoxide anion in vascular cells. Several experimental observations have shown an enhanced superoxide generation as a result of the activation of vascular NAD(P)H oxidase in hypertension. Although this enzyme responds to stimuli such as vasoactive factors, growth factors, and cytokines, some recent data suggest the existence of a genetic background modulating the expression of its different components. New polymorphisms have been identified in the promoter of the p22(phox) gene, an essential subunit of NAD(P)H oxidase, influencing the activity of this enzyme. Genetic investigations of these polymorphisms will provide novel markers for determination of genetic susceptibility to oxidative stress in hypertension.
Hypertension 2001 Dec 01
PMID:Oxidative stress in arterial hypertension: role of NAD(P)H oxidase. 1175 24

In patients with cyclosporine-induced hypertension, upregulation of the nitric oxide system and oxidative stress were shown, which could induce hypertension, remodeling, and chronic rejection by increasing nitric oxide catabolism. However, it is still debated whether cyclosporine and tacrolimus exert a different action. The aim of the current study was to compare the effects of cyclosporine and tacrolimus on markers of oxidative stress and endothelial dysfunction in kidney transplant patients with posttransplant hypertension. Monocyte p22, a NADH/NADPH system subunit, transforming growth factor-beta (TGF-beta), heme oxygenase-1 (HO-1), and endothelial NOS gene expression were measured in 16 patients. Angiotensin II is a potent stimulator of oxidative stress and angiotensin-converting enzyme inhibition may blunt this effect. Therefore, the same parameters were measured before and after 2 months of treatment with ramipril (5 mg/d). At baseline, in cyclosporine-and tacrolimus-treated patients, p22 and TGF-beta mRNA were similarly increased in comparison with normotensive healthy controls (0.90 +/- 0.05 d.u. and 0.83 +/- 0.05 in cyclosporine, 0.89 +/- 0.07 and 0.84 +/- 0.05 in tacrolimus; 0.53 +/- 0.07 and 0.75 +/- 0.03 in controls, respectively; p < 0.001). Endothelial NOS mRNA was increased in cyclosporine-and tacrolimus-treated patients in comparison with controls (0.92 +/- 0.09, 0.96 +/- 0.04, and 0.37 +/- 0.05 respectively; p < 0.001), whereas no difference was found between patients and controls in HO-1 mRNA. Ramipril reduced blood pressure (from 140 +/- 11/91 +/- 7 mm Hg to 129 +/- 6/85 +/- 5 mm Hg in cyclosporine and from 138 +/- 7/92 +/- 7 mm Hg to 127 +/- 10/82 +/- 6 mm Hg in tacrolimus group; p < 0.02 with no difference between groups). Ramipril also reduced p22 (to 0.83 +/- 0.05 in cyclosporine, p < 0.03 and to 0.81 +/- 0.08 in tacrolimus; p < 0.01) and TGF-beta mRNA (to 0.72 +/- 01 in cyclosporine, p < 0.02, and to 0.73 +/- 0.05 in tacrolimus; p < 0.01) with no difference between groups, but it did not change HO-1 and ecNOS mRNA. Cyclosporine and tacrolimus induce a comparable oxidative stress in kidney transplant patients with posttransplant hypertension. The association of ramipril normalizes blood pressure and reduces the oxidative stress induced by both drugs.
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PMID:Oxidative stress in kidney transplant patients with calcineurin inhibitor-induced hypertension: effect of ramipril. 1235 26

Increased reactive oxygen species (ROS) production is implicated in the pathophysiology of left ventricular (LV) hypertrophy and heart failure. However, the enzymatic sources of myocardial ROS production are unclear. We examined the expression and activity of phagocyte-type NADPH oxidase in LV myocardium in an experimental guinea pig model of progressive pressure-overload LV hypertrophy. Concomitant with the development of LV hypertrophy, NADPH-dependent O2- production in LV homogenates, measured by lucigenin (5 micro mol/L) chemiluminescence or cytochrome c reduction assays, significantly and progressively increased (by approximately 40% at the stage of LV decompensation; P<0.05). O2- production was fully inhibited by diphenyleneiodonium (100 micromol/L). Immunoblotting revealed a progressive increase in expression of the NADPH oxidase subunits p22(phox), gp91(phox), p67(phox), and p47(phox) in the LV hypertrophy group, whereas immunolabeling studies indicated the presence of oxidase subunits in cardiomyocytes and endothelial cells. In parallel with the increase in O2- production, there was a significant increase in activation of extracellular signal-regulated kinase 1/2, extracellular signal-regulated kinase 5, c-Jun NH2-terminal kinase 1/2, and p38 mitogen-activated protein kinase. These data indicate that an NADPH oxidase expressed in cardiomyocytes is a major source of ROS generation in pressure overload LV hypertrophy and may contribute to pathophysiological changes such as the activation of redox-sensitive kinases and progression to heart failure.
Hypertension 2002 Oct
PMID:Activation of NADPH oxidase during progression of cardiac hypertrophy to failure. 1236 50

The NO/superoxide (O2-) balance is a key regulator of endothelial function. O2- levels are elevated in many forms of cardiovascular disease; therefore, decreasing O2- should improve endothelial function. To explore this hypothesis, internal mammary arteries and saphenous veins, obtained from patients undergoing coronary artery revascularization, and aortic and carotid arteries from Wistar-Kyoto and spontaneously hypertensive stroke-prone rats were incubated with O2- dismutase or NAD(P)H oxidase inhibitors. O2- levels were measured using lucigenin chemiluminescence; NO bioavailability was assessed in organ chambers; and mRNA expression of NAD(P)H oxidase components was quantified by use of a Light Cycler. In rat arteries, phenylarsine oxide, 4-(2-aminoethyl)-benzenesulfanyl fluoride, and apocynin all decreased NADH-stimulated O2- production, but only apocynin increased NO bioavailability. In human internal mammary arteries and saphenous veins, apocynin decreased NAD(P)H-stimulated O2- generation and caused vasorelaxation that was endothelium dependent and reversed on addition of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. In addition, it increased NO production from cultured human endothelial saphenous vein cells. Polyethylene-glycolated O2- dismutase also increased NO bioavailability in rat carotid arteries and human blood vessels, but the effects were smaller than those observed with apocynin. NADH-generated O2- and mRNA expression of p22(phox), gp91(phox), and nox-1 were comparable between the 2 strains of rat. This is the first study to demonstrate pharmacological effects of apocynin in human blood vessels. The increases in NO bioavailability shown here suggest that the NAD(P)H oxidase pathway may be a novel target for drug intervention in cardiovascular disease.
Hypertension 2002 Nov
PMID:NAD(P)H oxidase inhibition improves endothelial function in rat and human blood vessels. 1241 73

The p22(phox) subunit is an essential protein in the activation of NAD(P)H oxidase. Here we report the preliminary characterisation of the human p22(phox) gene promoter. The p22(phox) promoter contains TATA and CCAC boxes and Sp1, gamma-interferon and nuclear factor kappaB sites. We screened for mutations in the p22(phox) promoter and identified a new polymorphism, localised at position -930 from the ATG codon, which was associated with hypertension. Mutagenesis experiments showed that the G allele had higher promoter activity than the A allele. These results suggest that the -930(A/G) polymorphism in the p22(phox) promoter may be a novel genetic marker associated with hypertension.
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PMID:Preliminary characterisation of the promoter of the human p22(phox) gene: identification of a new polymorphism associated with hypertension. 1272 92


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