Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endogenous oxygen- and nitrogen-centered free radicals are considered to play a decisive role in a variety of diseases such as neurodegenerative disorders, atherosclerosis, or cancer. Directly operating antioxidants limit the action of freely diffusing radicals by scavenging the attacking, oxidizing radical and re-reducing the oxidized biomolecule, i.e., the biomolecule-derived radical. From textbooks of biochemistry it is understood that NAD(P)H acts as a hydride (hydrogen anion) donor in a variety of enzymatic processes. One example is the re-reduction of GSSG to GSH, catalyzed by glutathione reductase. Because of this reaction, NADPH has been suggested to also act as an indirectly operating antioxidant, thus maintaining the antioxidative power of glutathione. To the best of our knowledge, however, neither NADPH nor NADH has been considered to be directly operating antioxidants. Based on recently published data, new experiments, and theoretical considerations, we propose that NAD(P)H represents a decisive, directly operating antioxidant that should be considered of major importance in the mitochondrial compartment. NAD(P)H fulfills this task both by scavenging toxic free radicals and repairing biomolecule-derived radicals.
 ...
PMID:NAD(P)H, a directly operating antioxidant? 1142 89

The nicotinamide adenine dinucleotide (NADH)/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system is a major source of superoxide anion (.O2-) production in the human vasculature and may therefore influence lipid peroxidation and severity of atherosclerosis. This study aimed to investigate a hypothetical influence of the p22 phox C242T polymorphism on the generation of malondialdehyde (MDA), extent and clinical onset of coronary artery disease (CAD) in patients. We studied 108 male Caucasians with angiographically documented CAD and 45 controls free of vascular disease under 60 years of age. p22 phox C242T genotypes and MDA levels were determined. Additional information was obtained from each subject on classic risk factors and clinical events of CAD. Genotype distribution in CAD-patients and controls was thymine-thymine (TT): 13.8% (13.3%), cytosine-thymine (CT): 46.3% (53.3%) and cytosine-cytosine (CC): 39.8% (33.3%), respectively. No significant influence was seen of the p22 phox C242T polymorphism on corresponding mean MDA levels in both groups. Furthermore, age at onset of first time angina pectoris (AP) and myocardial infarction (MCI) was not significantly different between genotype groups. It is concluded that the C242T polymorphism of the p22 phox gene is not associated with lipid peroxidation as measured by MDA, and is not a genetic risk marker for CAD Caucasians.
 ...
PMID:NADH/NADPH oxidase p22 phox C242T polymorphism and lipid peroxidation in coronary artery disease. 1172 80

Sialic acid containing glycosphingolipids (gangliosides) are expressed on the surface of all mammalian cells and have been implicated in regulating various biological phenomena; however, the detailed signaling mechanisms involved in this process are not known. We report here a novel aspect of disialoganglioside, GD3-mediated regulation of cell proliferation and cell death via the recruitment of reactive oxygen species (ROS). A low concentration (2.5-10 microm) of GD3, incubated with human aortic smooth muscle cells for a short period of time (10-30 min), stimulates superoxide generation via the activation of both NADPH oxidase and NADH oxidase activity. This leads to downstream signaling leading to cell proliferation and apoptosis. However, [(3)H]GD3 incubated with the cells under such conditions was found in a trypsin-sensitive fraction that was separable from endogenous GD3. The exact mechanism causing ROS generation and downstream signaling remains to be elucidated. The uptake of GD3 was accompanied by a 2.5-fold stimulation in the activity of mitogen-activated protein (MAP) kinase and 5-fold stimulation in cell proliferation. Preincubation of cells with membrane-permeable antioxidants, pyrrolidine dithiocarbamate, and N-acetylcysteine abrogated the superoxide generation and cell proliferation. In contrast, at higher concentrations (50-200 microm) GD3 inhibited the generation of superoxides but markedly stimulated the generation of nitric oxide (NO) (10-fold compared with control). This in turn stimulated mitochondrial cytochrome c release and intrachromosomal DNA fragmentation, which lead to apoptosis. In sum, at a low concentration, GD3 recruits superoxides to activate p44 MAPK and stimulates cell proliferation. In contrast, at high concentrations GD3 recruits nitric oxide to scavenge superoxide radicals that triggered signaling events that led to apoptosis. These observations might have relevance in regard to the potential role of GD3 in aortic smooth muscle cell proliferation and apoptosis that may contribute to plaque rupture in atherosclerosis.
 ...
PMID:GD3 recruits reactive oxygen species to induce cell proliferation and apoptosis in human aortic smooth muscle cells. 1186 54

Endothelial dysfunction and remodeling of the vessel wall of large and small arteries is associated with hypertension and other risk factors for cardiovascular disease. These changes alter vascular function and mechanics, aggravate high blood pressure (BP), and may accelerate the progression of atherosclerosis. Activation of oxidative stress by angiotensin II is a key component of this process. Angiotensin II stimulates nicotinamide adenine dinucleotide phosphate (NADPH)/nicotinamide adenine dinucleotide (NADH) oxidase in endothelium, smooth muscle cells, and the adventitia of blood vessels to generate reactive oxygen species, leading to endothelial dysfunction, growth, and inflammation. Upregulation of endothelin-1, adhesion molecules, nuclear factor-kappaB, and other inflammatory mediators, as well as increased breakdown of nitric oxide and uncoupling of nitric oxide synthase, contribute to the progression of vascular disease and atherogenesis. Clinical studies in which treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) was used demonstrated correction of some of the changes in large and small arteries in hypertensive subjects, whereas identical BP lowering with beta-blockers had no effect on endothelial function. In experimental models of atherosclerosis, ARBs, including losartan potassium, valsartan, and olmesartan medoxomil, have demonstrated the ability to prevent the progression of atherosclerosis. This was in part associated with decreased expression of inflammatory mediators and improved endothelial function. Blockade of the renin-angiotensin-aldosterone system with ACE inhibitors or ARBs appears to blunt both the development and progression of vascular disease in both small and large vessels in experimental models and in humans beyond the effect of these agents on BP. This may help to explain the positive results of recently completed trials such as Heart Outcomes Prevention Evaluation (HOPE) and Losartan Intervention for Endpoint Reduction in Hypertension (LIFE).
 ...
PMID:Beyond blood pressure: the endothelium and atherosclerosis progression. 1238 92

Angiotensin II(AngII) activates NADH/NAPDH oxidase activity and stimulates reactive oxygen species(ROS) production, which induces many proinflammatory genes such as vascular cell adhesion molecule-1(VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1(MCP-1) mainly via AngII type I receptor(AT1). ROS are important in cardiovascular disease because many of these preinflammatory cytokines play a critical role in the initiation and progression of atherosclerosis. AT1 receptor blockade is important to prevent cardiovascular disease. AngII type 1 receptor blocker(ARB) and/or AngII converting enzyme inhibitor(ACEI) are useful for preventing cardiovascular disease. The role of AngII type II receptor(AT2) for producing ROS and/or cardiovascular damage has been studied.
 ...
PMID:[Angiotensin II receptor and oxidative stress]. 1239 80

This study investigated the effects of the natural polyphenol mangiferin (MA) on superoxide anion (O(2)(-)) production, xanthine oxidase (XO) activity, vascular contractility, inducible nitric oxide synthase (iNOS) mRNA levels, tumour necrosis factor-alpha (TNF-alpha) mRNA levels, and tumour growth factor-beta (TGF-beta) mRNA levels. O(2)(-) was generated by the hypoxanthine-xanthine oxidase (HX-XO) and phenazine methosulphate (PMS)-NADH systems. XO activity was determined by measurement of uric acid production with xanthine as substrate. Vascular contraction experiments were performed with intact rat aortic rings. iNOS, TNF-alpha and TGF-beta gene expression in rat macrophages stimulated in vivo with 3% thioglycollate and in vitro with 100 ng/mL lipopolysaccharide and 10U/mL of interferon-gamma were evaluated semiquantitatively by the retrotranscriptase-polymerase chain reaction. MA at 10-100 microM, like the known O(2)(-) scavenger superoxide dismutase (1U/mL), scavenged O(2)(-) produced by the HX/XO and PMS-NADH systems. By contrast MA at 1-100 microM, unlike allopurinol (10 microM), was unable to inhibit XO activity. MA at 1-100 microM did not modify resting tone or the contractile responses elicited by 1 microM phenylephrine or 1 microM phorbol 12-myristate 13-acetate in rat aorta. MA at 1-100 microM, like dexamethasone (100 microM), decreased iNOS mRNA levels in activated macrophages. At 100 microM, MA also reduced TNF-alpha mRNA levels, but increased TGF-beta mRNA levels. These results thus indicate that MA is an O(2)(-) scavenger and that it inhibits expression of the iNOS and TNF-alpha genes, suggesting that it may be of potential value in the treatment of inflammatory and/or neurodegenerative disorders. In addition, the finding that MA enhances TGF-beta gene expression suggests that this polyphenol might also be of value in the prevention of cancer, autoimmune disorders, atherosclerosis and coronary heart disease.
 ...
PMID:In vitro effects of mangiferin on superoxide concentrations and expression of the inducible nitric oxide synthase, tumour necrosis factor-alpha and transforming growth factor-beta genes. 1269 77

A substantial proportion of individuals with coronary artery disease (CAD) has concomitant hypercholesterolemia. A large-scale association study was performed to identify separately genes that confer susceptibility to CAD in the absence or presence of nonfamilial hypercholesterolemia. The study population comprised 5248 unrelated Japanese individuals, including 3085 subjects with CAD (2350 men, 735 women) and 2163 controls (1329 men, 834 women). Among all study subjects, 2541 individuals (1688 men, 853 women) had nonfamilial hypercholesterolemia, and 2707 individuals (1991 men, 716 women) did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hyperuricemia revealed that three polymorphisms [994G --> T (Val279Phe) in the platelet-activating factor acetylhydrolase gene, 242C --> T (His72Tyr) in the NADH/NADPH oxidase p22 phox gene, and 1100C --> T in the apolipoprotein C-III gene] were significantly associated with CAD in men with hypercholesterolemia. Genotyping of these three polymorphisms may prove informative for prediction of the genetic risk for CAD in men with nonfamilial hypercholesterolemia.
Atherosclerosis 2004 Jan
PMID:Association of gene polymorphisms with coronary artery disease in individuals with or without nonfamilial hypercholesterolemia. 1470 72

Hypertension is a risk factor for cardiovascular and cerebrovascular outcome. Hypertension is associated with oxidative stress. Alteration in endothelial function is an initial step in the pathogenesis of atherosclerosis. A balance between ambient levels of super oxide and released nitric oxide(NO) plays an important role in the maintenance of endothelial function. It is well known that reactive oxygen species, including hydroxy radicals, directly scavenge NO and produce toxic peroxynitrite. Angiotensin II and mechanical stress generate the reactive oxygen species through the activation of NADH/NADPH oxidase in hypertension. Several investigators have shown that oxidative stress is involved in enhanced vascular growth, vascular inflammation, and impaired endothelium-dependent in hypertension. In this review, we would like to explain the role of oxidative stress in hypertensive organ damages.
 ...
PMID:[Oxidative stress, reactive oxygen species]. 1473 35

Plain old balloon angioplasty (POBA) is a useful therapeutic strategy especially for angioplasty of small coronary arteries. An association study was performed to identify genes that confer susceptibility to restenosis after POBA. The study population comprised 730 individuals (424 men, 306 women) who underwent successful POBA in at least one major coronary artery and were examined angiographically 6 months after the procedure. A total of 469 subjects (273 men, 196 women) exhibited no restenosis after POBA for any of the coronary lesions, whereas 261 subjects (151 men, 110 women) manifested restenosis for all lesions. The genotypes for 40 polymorphisms of 34 genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that two polymorphisms (242C --> T in the NADH/NADPH oxidase p22 phox (p22-PHOX) gene and 2136C --> T in the thrombomodulin (THBD) gene) in men and two polymorphisms (584G --> A in the paraoxonase 1 (PON1) gene and 2445G --> A in the fatty acid-binding protein 2 (FABP2) gene) in women were significantly associated with restenosis after POBA. A stepwise forward selection procedure revealed that the effects of these polymorphisms on restenosis were statistically independent of conventional risk factors for coronary artery disease. Genotyping of these polymorphisms may prove informative for assessment of genetic risk for restenosis after POBA.
Atherosclerosis 2004 May
PMID:Genetic risk for restenosis after coronary balloon angioplasty. 1513 68

NAD(P)H oxidase contributes to the pathogenesis of cancer and cardiovascular diseases such as hypertension, atherosclerosis, restenosis, cardiac hypertrophy and heart failure. Plumbagin, a plant-derived naphthoquinone, has been shown to exert anticarcinogenic and anti-atherosclerosis effects in animals. However, the molecular mechanisms underlying these effects remain unknown. It is possible that the beneficial effect of plumbagin is due to the inhibition of NAD(P)H oxidase. Human embryonic kidney 293 (HEK293) and brain tumour LN229 cells express mainly Nox-4, a renal NAD(P)H oxidase. We have examined the effect of plumbagin on Nox-4 activity in HEK293 and LN229 cells using lucigenin-dependent chemiluminescence assay. Plumbagin inhibited the activity of Nox-4 in a time- and dose-dependent manner in HEK293 and LN229 cells. Production of superoxide in HEK293 cells was inhibited by diphenyleneiodonium (DPI), a NAD(P)H oxidase inhibitor. The superoxide production in HEK293 cells was NADPH- and NADH-dependent indicating that the superoxide was generated by a NAD(P)H oxidase in HEK293 cells, but not by the redox-cycling of lucigenin. Furthermore, plumbagin inhibited the superoxide production in Nox-4 transfected COS-7 cells. These results indicated that plumbagin directly interacted with Nox-4 and inhibited its activity.
 ...
PMID:Inhibition of Nox-4 activity by plumbagin, a plant-derived bioactive naphthoquinone. 1563 99


<< Previous 1 2 3 4 5 6 7 Next >>