Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with arrhythmogenesis and sudden cardiac death (SCD). Hcy decreases constitutive neuronal and endothelial nitric oxide (NO), and cardiac diastolic relaxation. Hcy increases the iNOS/NO, peroxynitrite, mitochondrial NADPH oxidase, and suppresses superoxide dismutase (SOD) and redoxins. Hcy activates matrix metalloproteinase (MMP), disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) disrupt the normal pattern of cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling, leading to a pro-arrhythmic environment. The goal of this review is to elaborate the mechanism of Hcy-mediated iNOS/NO in E-M uncoupling and SCD. It is known that Hcy creates arrhythmogenic substrates (i.e. increase in collagen/elastin ratio and disruption in connexin-43) and exacerbates heart failure during chronic volume overload. Also, Hcy behaves as an agonist to N-methyl-D-aspartate (NMDA, an excitatory neurotransmitter) receptor-1, and blockade of NMDA-R1 reduces the increase in heart rate-evoked by NMDA-analog and reduces SCD. This review suggest that Hcy increases iNOS/NO, superoxide, metalloproteinase activity, and disrupts connexin-43, exacerbates endothelial-myocyte uncoupling and cardiac failure secondary to inducing NMDA-R1.
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PMID:Arrhythmia and neuronal/endothelial myocyte uncoupling in hyperhomocysteinemia. 1717 94

Hyperhomocysteinemia is a recognized risk factor for vascular disease, but pathogenetic mechanisms involved in its vascular actions are largely unknown. Because VCAM-1 expression is crucial in monocyte adhesion and early atherogenesis, we evaluated the NF-kappaB-related induction of VCAM-1 by homocysteine (Hcy) and the possible inhibitory effect of dietary polyphenolic antioxidants, such as trans-resveratrol (RSV) and hydroxytyrosol (HT), which are known inhibitors of NF-kappaB-mediated VCAM-1 induction. In human umbilical vein endothelial cells (HUVEC), Hcy, at 100 micromol/l, but not cysteine, induced VCAM-1 expression at the protein and mRNA levels, as shown by enzyme immunoassay and Northern analysis, respectively. Transfection studies with deletional VCAM-1 promoter constructs demonstrated that the two tandem NF-kappaB motifs in the VCAM-1 promoter are necessary for Hcy-induced VCAM-1 gene expression. Hcy-induced NF-kappaB activation was confirmed by EMSA, as shown by the nuclear translocation of its p65 (RelA) subunit and the degradation of the inhibitors IkappaB-alpha and IkappaB-beta by Western analysis. Hcy also increased intracellular reactive oxygen species by NAD(P)H oxidase activation, as shown by the membrane translocation of its p47(phox) subunit. NF-kappaB inhibitors decreased Hcy-induced intracellular reactive oxygen species and VCAM-1 expression. Finally, we found that nutritionally relevant concentrations of RSV and HT, but not folate and vitamin B6, reduce (by >60% at 10(-6) mol/l) Hcy-induced VCAM-1 expression and monocytoid cell adhesion to the endothelium. These data indicate that pathophysiologically relevant Hcy concentrations induce VCAM-1 expression through a prooxidant mechanism involving NF-kappaB. Natural Mediterranean diet antioxidants can inhibit such activation, suggesting their possible therapeutic role in Hcy-induced vascular damage.
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PMID:Homocysteine induces VCAM-1 gene expression through NF-kappaB and NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants. 1758 18

Elevation of blood homocysteine (Hcy) levels (hyperhomocysteinemia) is a risk factor for cardiovascular disorders. We previously reported that oxidative stress contributed to Hcy-induced inflammatory response in vascular cells. In this study, we investigated whether NADPH oxidase was involved in Hcy-induced superoxide anion accumulation in the aorta, which leads to endothelial dysfunction during hyperhomocysteinemia. Hyperhomocysteinemia was induced in rats fed a high-methionine diet. NADPH oxidase activity and the levels of superoxide and peroxynitrite were markedly increased in aortas isolated from hyperhomocysteinemic rats. Expression of the NADPH oxidase subunit p22 phox increased significantly in these aortas. Administration of an NADPH oxidase inhibitor (apocynin) not only attenuated aortic superoxide and peroxynitrite to control levels but also restored endothelium-dependent relaxation in the aortas of hyperhomocysteinemic rats. Transfection of human endothelial cells or vascular smooth muscle cells with p22 phox siRNA to inhibit NADPH oxidase activation effectively abolished Hcy-induced superoxide anion production, thus indicating the direct involvement of NADPH oxidase in elevated superoxide generation in vascular cells. Taken together, these results suggest that Hcy-stimulated superoxide anion production in the vascular wall is mediated through the activation of NADPH oxidase, which leads to endothelial dysfunction during hyperhomocysteinemia.
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PMID:Homocysteine stimulates NADPH oxidase-mediated superoxide production leading to endothelial dysfunction in rats. 1806 25

Despite substantial evidence indicating the association of hyperhomocysteinemia (hHcys) and end-stage renal disease (ESRD), the pathogenic role of increased plasma homocysteine (Hcys) levels in the progression of ESRD remains unclear. This review will briefly summarize recent findings regarding the role of hHcys in the development of glomerulosclerosis, the association of hHcys with reduced renal transsulfuration and Hcys-induced changes of redox signaling in the development of glomerulosclerosis in rat kidneys. Based on these results, it is concluded that hHcys is implicated in glomerular sclerosis in hypertension, elevated plasma Hcys in Dahl salt-sensitive (SS) hypertensive rats is due to downregulation of cystathionine beta-synthase (CBS) expression and consequent abnormality of transsulfuration in the kidney compared with normotensive rats. Hcys-induced superoxide (O(2)(*-)) production by activation of NADPH oxidase as a triggering mechanism contributes to the effects of Hcys on the homeostasis of extracellular matrix and consequent sclerosis in the glomeruli, and NADPH oxidase activation by Hcys is associated with enhanced Rac GTPase activity.
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PMID:Hyperhomocysteinemia: association with renal transsulfuration and redox signaling in rats. 1806 50

Cystathionine beta synthase deficiency induces hyperhomocysteinemia which is considered as a risk factor for vascular diseases. Studies underlined the importance of altered cellular redox reactions in hyperhomocysteinemia-induced vascular pathologies. Nevertheless, hyperhomocysteinemia also induces hepatic dysfunction which may accelerate the development of vascular pathologies by modifying cholesterol homeostasis. The aim of the present study was to analyze the modifications of redox state in the liver of heterozygous cystathionine beta synthase-deficient mice, a murine model of hyperhomocysteinemia. In this purpose, we quantified levels of reactive oxygen and nitrogen species and we assayed activities of main antioxidant enzymes. We found that cystathionine beta synthase deficiency induced NADPH oxidase activation. However, there was no accumulation of reactive oxygen (superoxide anion, hydrogen peroxide) and nitrogen (nitrite, peroxynitrite) species. On the contrary, hepatic hydrogen peroxide level was decreased independently of an activation of glutathione-dependent mechanisms. In fact, cystathionine beta synthase deficiency had no effect on glutathione peroxidase, glutathione reductase and glutathione S-transferase activities. However, we found a 50% increase in hepatic catalase activity without any variation of expression. These findings demonstrate that cystathionine beta synthase deficiency initiates redox disequilibrium in the liver. However, the activation of catalase attenuates oxidative impairments.
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PMID:Cystathionine beta synthase deficiency induces catalase-mediated hydrogen peroxide detoxification in mice liver. 1854 Nov 57

We have previously shown that homocysteine (Hcy) can induce monocyte chemoattractant protein-1 (MCP-1) secretion via reactive oxygen species (ROS) in human monocytes. Here, we show that Hcy upregulates expression of an important antioxidative protein, thioredoxin (Trx), via NADPH oxidase in human monocytes in vitro. The increase of Trx expression and activity inhibited Hcy-induced ROS production and MCP-1 secretion. Of note, 2-week hyperhomocysteinemia (HHcy) ApoE(-/-) mice showed accelerated lesion formation and parallel lower Trx expression in macrophages than ApoE(-/-) mice, suggesting that HHcy-induced sustained oxidative stress in vivo might account for impaired Trx and hence increased ROS production and MCP-1 secretion from macrophages, and subsequently accelerated atherogenesis.
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PMID:Regulatory role of thioredoxin in homocysteine-induced monocyte chemoattractant protein-1 secretion in monocytes/macrophages. 1897 55

We currently reported that Vav2, a member of the guanine nucleotide exchange factor-Vav subfamily, participates in homocysteine-induced increases in Rac1 activity and consequent activation of NADPH oxidase in rat mesangial cells. However, the physiological relevance of this cellular action of Vav2 remains unknown. The present study tested a hypothesis that Vav2 importantly mediates the injurious action of homocysteine on glomeruli and thereby contributes to the development of glomerulosclerosis during hyperhomocysteinemia. We found that, among Vav members, Vav2 was abundantly expressed in glomeruli. When Vav2 short hairpin RNA was transfected into the kidneys of Sprague-Dawley rats, hyperhomocysteinemia induced by folate-free diet failed to significantly enhance Rac1 activity and increase NADPH-dependent superoxide production. In these rats with silenced renal Vav2 gene, glomerular injury during hyperhomocysteinemia was markedly attenuated compared with those rats only receiving mock vector transfection, as shown by ameliorated albuminuria and extracellular matrix metabolism. In the rat kidneys with transfection of a dominant-active Vav2 variant (onco-Vav2), we found that overexpression of Vav2 led to significant increases in Rac1 activity, superoxide production, and glomerular injury, which was similar to that induced by hyperhomocysteinemia. However, this Vav2 overexpression was unable to further enhance homocysteine-induced glomerular injury. We concluded that Vav2-mediated activation of NADPH oxidase is an important initiating mechanism resulting in hyperhomocysteinemic glomerular injury through enhanced local oxidative stress.
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PMID:Contribution of guanine nucleotide exchange factor Vav2 to hyperhomocysteinemic glomerulosclerosis in rats. 1902 89

Hyperhomocysteinaemia has been associated with increased risk of thrombosis and atherosclerosis. Homocysteine produces endothelial injury and stimulates platelet aggregation. Several molecular mechanisms related to these effects have been elucidated. The study aimed to deeply investigate the homocysteine effect on nitric oxide formation in human platelets. The homocysteine-induced changes on nitric oxide, cGMP, superoxide anion levels and nitrotyrosine formation were evaluated. The enzymatic activity and the phosphorylation status of endothelial nitric oxide synthase (eNOS) at thr495 and ser1177 residues were measured. The protein kinase C (PKC), assayed by immunofluorescence confocal microscopy technique and by phosphorylation of p47pleckstrin, and NADPH oxidase activation, tested by the translocation to membrane of the two cytosolic subunits p47(phox) and p67(phox), were assayed. Results show that homocysteine reduces platelet nitric oxide and cGMP levels. The inhibition of eNOS activity and the stimulation of NADPH oxidase primed by PKC appear to be involved. PKC stimulates the eNOS phosphorylation of the negative regulatory residue thr495 and the dephosphorylation of the positive regulatory site ser1177. GF109203X and U73122, PKC and phospholipase Cgamma2 pathway inhibitors, respectively, reverse this effect. Moreover, homocysteine stimulates superoxide anion elevation and NADPH oxidase activation. These effects are significantly decreased by GF109203X and U73122, suggesting the involvement of PKC in NADPH oxidase activation. Homocysteine induces formation of the peroxynitrite biomarker nitrotyrosine. Taken together these results suggest that the homocysteine-mediated responses leading to nitric oxide impairment are mainly coupled to PKC activation. Thus homocysteine stimulates platelet aggregation and decreases nitric oxide bioavailability.
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PMID:Homocysteine decreases platelet NO level via protein kinase C activation. 1910 Aug 55

Epidemiological and experimental studies have correlated hyperhomocysteinemia to a range of neurodegenerative conditions, including Alzheimer's disease, stroke, and Parkinson's disease. Although homocysteine-induced apoptosis in neurons has been extensively studied, little information is available regarding the effect of homocysteine on microglia. In this report, we demonstrated that homocysteine promoted proliferation and up-regulated the expression of CD11b (a marker of microglial activation). Consistent with our in vitro results, a significant increase in the number of CD11b-positive microglia was also observed in brain sections of mice with hyperhomocysteinemia. Homocysteine promoted the activity of NAD(P)H oxidases, resulting in the generation of reactive oxygen species. Up-regulation of NAD(P)H oxidase activity by homocysteine appears to be due to its ability to induce the phosphorylation of p47phox through the p38 MAPK pathway. Furthermore, inhibition of reactive oxygen species significantly blocked cellular proliferation and activation in microglia. Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases.
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PMID:Homocysteine promotes proliferation and activation of microglia. 1913 Nov 43

Our recent studies have indicated that hyperhomocysteinemia (hHcys) may induce podocyte damage, resulting in glomerulosclerosis. However, the molecular mechanisms mediating hHcys-induced podocyte injury are still poorly understood. In the present study, we first demonstrated that an intact NADPH oxidase system is present in podocytes as shown by detection of its membrane subunit (gp91(phox)) and cytosolic subunit (p47(phox)). Then, confocal microscopy showed that gp91(phox) and p47(phox) could be aggregated in lipid raft (LR) clusters in podocytes treated with homocysteine (Hcys), which were illustrated by their colocalization with cholera toxin B, a common LR marker. Different mechanistic LR disruptors, either methyl-beta-cyclodextrin (MCD) or filipin abolished such Hcys-induced formation of LR-gp91(phox) or LR-p47(phox) transmembrane signaling complexes. By flotation of detergent-resistant membrane fractions we found that gp91(phox) and p47(phox) were enriched in LR fractions upon Hcys stimulation, and such enrichment of NADPH oxidase subunits and increase in its enzyme activity were blocked by MCD or filipin. Functionally, disruption of LR clustering significantly attenuated Hcys-induced podocyte injury, as shown by their inhibitory effects on Hcys-decreased expression of slit diaphragm molecules such as nephrin and podocin. Similarly, Hcys-increased expression of desmin was also reduced by disruption of LR clustering. In addition, inhibition of such LR-associated redox signaling prevented cytoskeleton disarrangement and apoptosis induced by Hcys. It is concluded that NADPH oxidase subunits aggregation and consequent activation of this enzyme through LR clustering is an important molecular mechanism triggering oxidative injury of podocytes induced by Hcys.
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PMID:Redox signaling via lipid raft clustering in homocysteine-induced injury of podocytes. 2003 96


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