Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous reports on the molecular mechanism of atherogenesis indicate an increase in oxidative stress, formation of advanced glycoxidation end products (AGEs), chronic inflammation, and activated cellular response particularly in diabetic patients. To elucidate the initiating and early accelerating events this review will focus on the molecular causes of the induction of these stress factors, their interactions, and their contribution to atherogenesis. Metabolic factors such as elevated free fatty acids, high glucose levels or AGEs induce reactive oxygen species (ROS) in vascular cells leading to ongoing AGE formation and to gene induction of proinflammatory cytokines. Vice versa, numerous cytokines found elevated in obesity and diabetes may also induce oxidative stress thus a circulus vitious may be initiated and accelerated. Increased production of ROS, mainly from mitochondria and NAD(P)H oxidase, stimulates signaling cascades including protein kinase C and mitogen-activated protein kinase pathway leading to nuclear translocation of transcription factors such as nuclear factor-kappaB (NF-kappaB), activator protein 1, and specificity protein 1. Subsequently, the expression of numerous genes including cytokines is rapidly induced, which, in turn, may act on vascular cells promoting the deleterious effects. From animal models of accelerated atherosclerosis a causal role of NAD(P)H oxidase and the AGE/RAGE/NF-kappaB axis to atherogenesis is suggested. Because all factors involved form a highly interwoven network of interactions, the blockade of ROS or AGE formation at different sites may interrupt the vicious cycle. Promising candidate agents are, currently on trial. Most important to clinical practice, a number of drugs commonly used in the treatment of diabetes, hypertension, or cardiovascular disease, such as angiotensin-converting enzyme inhibitors, AT(1) receptor blockers, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins), and thiazolidindiones have shown promising 'preventive' intracellular antioxidant activity in addition to their primary pharmacological actions.
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PMID:Oxidative stress, AGE, and atherosclerosis. 1765 6

Activation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase by angiotensin II is integral to the formation of oxidative stress in the vasculature and the kidney. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibition is associated with reductions of oxidative stress in the vasculature and kidney and associated decreases in albuminuria. Effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition on oxidative stress in the kidney and filtration barrier integrity are poorly understood. To investigate, we used transgenic TG(mRen2)27 (Ren2) rats, which harbor the mouse renin transgene and renin-angiotensin system activation, and an immortalized murine podocyte cell line. We treated young, male Ren2 and Sprague-Dawley rats with rosuvastatin (20 mg/kg IP) or placebo for 21 days. Compared with controls, we observed increases in systolic blood pressure, albuminuria, renal NADPH oxidase activity, and 3-nitrotryosine staining, with reductions in the rosuvastatin-treated Ren2. Structural changes on light and transmission electron microscopy, consistent with periarteriolar fibrosis and podocyte foot-process effacement, were attenuated with statin treatment. Nephrin expression was diminished in the Ren2 kidney and trended to normalize with statin treatment. Angiotensin II-dependent increases in podocyte NADPH oxidase activity and subunit expression (NOX2, NOX4, Rac, and p22(phox)) and reactive oxygen species generation were decreased after in vitro statin treatment. These data support a role for increased NADPH oxidase activity and subunit expression with resultant reactive oxygen species formation in the kidney and podocyte. Furthermore, statin attenuation of NADPH oxidase activation and reactive oxygen species formation in the kidney/podocyte seems to play roles in the abrogation of oxidative stress-induced filtration barrier injury and consequent albuminuria.
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PMID:Attenuation of NADPH oxidase activation and glomerular filtration barrier remodeling with statin treatment. 1817 55

Previous studies suggest a reduction in cardiovascular risk among subjects expressing the glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49) deficient phenotype. We aimed to test this hypothesis in male subjects expressing the G6PD-deficient phenotype vs wild type G6PD. In a case-control study we examined consecutive patients admitted for acute myocardial infarction or unstable angina, and controls admitted for diagnoses other than coronary heart disease (CHD). The G6PD phenotype was determined by measuring the enzyme activity in erythrocytes, as the absorbance rate change due to NADPH reduction. The CHD risk associated with the G6PD phenotype was assessed with unconditional logistic regression. G6PD-deficient subjects were less frequently represented among cases (11.8%) than among controls (18.6%, p=0.002). The genetic condition of G6PD deficiency conveyed a significant reduction in CHD risk (OR=0.6; 95% CI 0.4 to 0.9). We confirm the hypothesis that subjects with the G6PD-deficient phenotype are less prone to CHD. We suggest that such a protective effect may be ascribable to a reduced 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA R) activity, a statin-like effect, as well as to a downregulation in NADPH oxidase activity with a consequent reduction in oxygen-free radical production.
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PMID:Glucose-6-phosphate dehydrogenase deficiency protects against coronary heart disease. 1839 52

Previous studies showed that homocysteine (Hcy) reduces endothelial progenitor cells (EPCs) numbers and impairs functional activity. Atorvastatin, HMG-CoA inhibition has been showed to have protective effects on EPCs. Recent studies have demonstrated that reduced EPCs numbers and activity are associated with EPCs apoptosis. However, the protective mechanisms of atorvastatin on HHcy-induced EPCs apoptosis remain to be determined. This study was designed to examine the effect of atorvastatin on homocysteine-induced reactive oxygen species (ROS) production and apoptosis in EPCs. EPCs were isolated from peripheral blood and characterized, then challenged with Hcy (50-500 micromol/L) in the presence or absence of atorvastatin (0.01-1 micromol/L) or various stress signaling inhibitors, including mevalonate (100 micromol/L), antioxidants N-acetyl cysteine (NAC, 10 micromol/L), the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (DPI 10 micromol/L), the eNOS inhibitor N(G)mono-methyl-l-arginine LNMA (1mmol/L), and the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 (10 micromol/L). Apoptosis was evaluated by FACS analysis and cell viability was determined by MTT assay. ROS were detected by 2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFH-DA). NADPH oxidases were evaluated with lucigenin-enhanced chemiluminescence. Expression of Nox4 mRNA and p-p38MAPK protein was measured by RT-PCR and Western blot analysis, respectively. Our data revealed that atorvastatin significantly suppressed Hcy-induced ROS accumulation and EPCs apoptosis. Atorvastatin also antagonized homocysteine-induced activation of NADPH oxidase and overexpression of Nox4 mRNA and p-p38MAPK protein. Similar effects occurred with EPCs transfected with Nox4 siRNA. These findings demonstrated that atorvastatin may inhibit Hcy-induced NADPH oxidase activation, ROS accumulation, and EPCs apoptosis through Nox4/p38MAPK dependent mechanisms, all of which may contribute to atorvastatin-induced beneficial effects on EPCs function.
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PMID:Atorvastatin inhibits homocysteine-induced oxidative stress and apoptosis in endothelial progenitor cells involving Nox4 and p38MAPK. 2001 84

Noise-induced hearing loss (NIHL) is one of the most common forms of sensorineural hearing loss and a well-known contributor to presbycusis. Based on the generation of reactive oxygen species (ROS) in the pathogenesis of NIHL, augmentation of the antioxidative defense system is a major target for pharmacological prevention. In this study, we assessed whether administration of pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, which is a rate-limiting enzyme of cholesterol synthesis, before noise exposure protects against cochlear injury in BALB/c mice. Noise exposure produced both compound threshold shift (CTS) and permanent threshold shift (PTS) over 40 dB at 16 and 32 kHz. Pretreatment with pravastatin (25 mg/kg) for 5 days significantly decreased both CTS and PTS. Pravastatin also reduced hair cell death after noise exposure in the cochlea, which was identified by surface preparation and scanning electron microscopy (SEM). It also reduced the formation of noise-induced 4-hydroxynonenal (4-HNE), a byproduct of lipid peroxidation. Activation of Rac1, one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, which is a major superoxide generator in the cell membrane, was inhibited by the administration of pravastatin. These findings suggest that pravastatin can protect against cochlear acoustic injury by lowering ROS generation via inhibition of the formation of the NADPH oxidase complex. This study will be helpful for the development of new therapeutic strategies for NIHL and other hearing loss-related diseases caused by ROS overproduction.
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PMID:Pravastatin attenuates noise-induced cochlear injury in mice. 2236 11

Since the discovery of the importance of nitric oxide (NO) to the human body three decades ago, numerous laboratory and clinical studies have been done to explore its potential therapeutic actions on many organs. In the cardiovascular system, NO works as a volatile signaling molecule regulating the vascular permeability and vascular tone, preventing thrombosis and inflammation, as well as inhibiting the smooth muscle hyperplasia. Thus, NO is important in the prevention and treatment of cardiovascular disease. NO is synthesized by NO synthase (NOS) with tetrahydrobiopterin (BH4) as the crucial cofactor. Many studies have been done to form nitric oxide donors so as to deliver NO directly to the vessel walls. In addition, NO moieties have been incorporated into existing therapeutic agents to enhance the NO bioavailability, including statins. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA), the rate-limiting enzyme of the mevalonate pathway. By inhibiting this pathway, statins lower blood cholesterol and exert their pleiotropic effects through activity in reaction cascades, such as Rho/ROCK and Rac 1/NADPH oxidase pathways. Statins have also been observed to implement their non-lipid effects by promoting BH4 synthesis with increase of NO bioavailability. Furthermore, NO-donating statins in laboratory studies have demonstrated to produce better therapeutic effects than their parent's drugs. They offer better anti-inflammatory, anti-proliferative and antithrombotic actions on cardiovascular system. They also cause better revascularization in peripheral ischemia and produce greater enhancement in limb reperfusion and salvage. In addition, it has been shown that NO-donating statin caused less myotoxicity, the most common side effect related to treatment with statins. The initial studies have demonstrated the superior therapeutic effects of NO-donating statins while producing fewer side effects.
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PMID:Recent developments in the effects of nitric oxide-donating statins on cardiovascular disease through regulation of tetrahydrobiopterin and nitric oxide. 2513 60