UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flavonoids containing phenol B rings, e.g. naringenin, naringin, hesperetin and apigenin, formed prooxidant metabolites that oxidised NADH upon oxidation by peroxidase/H2O2. Extensive oxygen uptake occurred which was proportional to the NADH oxidised and was increased up to twofold by superoxide dismutase. Only catalytic amounts of flavonoids and H2O2 were required indicating a redox cycling mechanism that activates oxygen and generates H2O2. NADH also prevented the oxidative destruction of flavonoids by peroxidase/H2O2 until the NADH was depleted. These results suggest that prooxidant phenoxyl radicals formed by these flavonoids cooxidise NADH to form NAD radicals which then activated oxygen. Similar oxygen activation mechanisms by other phenoxyl radicals have been implicated in the initiation of atherosclerosis and carcinogenesis by xenobiotic phenolic metabolites. This is the first time that a group of flavonoids have been identified as prooxidants independent of transition metal catalysed autoxidation reactions.
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PMID:Oxygen activation during peroxidase catalysed metabolism of flavones or flavanones. 1047 12

Reactive oxygen species have emerged as important molecules in cardiovascular function. Recent work has shown that NAD(P)H oxidases are major sources of superoxide in vascular cells and myocytes. The biochemical characterization, activation paradigms, structure, and function of this enzyme are now partly understood. Vascular NAD(P)H oxidases share some, but not all, characteristics of the neutrophil enzyme. In response to growth factors and cytokines, they produce superoxide, which is metabolized to hydrogen peroxide, and both of these reactive oxygen species serve as second messengers to activate multiple intracellular signaling pathways. The vascular NAD(P)H oxidases have been found to be essential in the physiological response of vascular cells, including growth, migration, and modification of the extracellular matrix. They have also been linked to hypertension and to pathological states associated with uncontrolled growth and inflammation, such as atherosclerosis.
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PMID:NAD(P)H oxidase: role in cardiovascular biology and disease. 1072 Apr 9

Superoxide anion plays important roles in vascular disease states. Increased superoxide production contributes to reduced nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of vascular disease. We measured superoxide production by NAD(P)H oxidase in human blood vessels and examined the relationships between NAD(P)H oxidase activity, NO-mediated endothelial function, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations and direct measurements of vascular superoxide production were determined in human saphenous veins obtained from 133 patients with coronary artery disease and identified risk factors. The predominant source of vascular superoxide production was an NAD(P)H-dependent oxidase. Increased vascular NAD(P)H oxidase activity was associated with reduced NO-mediated vasorelaxation. Furthermore, reduced endothelial vasorelaxations and increased vascular NAD(P)H oxidase activity were both associated with increased clinical risk factors for atherosclerosis. Diabetes and hypercholesterolemia were independently associated with increased NADH-dependent superoxide production. The association of increased vascular NAD(P)H oxidase activity with endothelial dysfunction and with clinical risk factors suggests an important role for NAD(P)H oxidase-mediated superoxide production in human atherosclerosis. The full text of this article is available at http://www.circresaha.org. Key Words:atherosclerosis endothelium superoxide nitric oxide diabetes Two Distinct Congenital Arrhythmias Evoked by a Multidysfunctional Na(+) Channel Marieke W. Veldkamp, Prakash C. Viswanathan, Connie Bezzina, Antonius Baartscheer, Arthur A.M. Wilde, Jeffrey R. Balser Abstract-The congenital long-QT syndrome (LQT3) and the Brugada syndrome are distinct, life-threatening rhythm disorders linked to autosomal dominant mutations in SCN5A, the gene encoding the human cardiac Na(+) channel. It is believed that these two syndromes result from opposite molecular effects: LQT3 mutations induce a gain of function, whereas Brugada syndrome mutations reduce Na(+) channel function. Paradoxically, an inherited C-terminal SCN5A mutation causes affected individuals to manifest electrocardiographic features of both syndromes: QT-interval prolongation (LQT3) at slow heart rates and distinctive ST-segment elevations (Brugada syndrome) with exercise. In the present study, we show that the insertion of the amino acid 1795insD has opposite effects on two distinct kinetic components of Na(+) channel gating (fast and slow inactivation) that render unique, simultaneous effects on cardiac excitability. The mutation disrupts fast inactivation, causing sustained Na(+) current throughout the action potential plateau and prolonging cardiac repolarization at slow heart rates. At the same time, 1795insD augments slow inactivation, delaying recovery of Na(+) channel availability between stimuli and reducing the Na(+) current at rapid heart rates. Our findings reveal a novel molecular mechanism for the Brugada syndrome and identify a new dual mechanism whereby single SCN5A mutations may evoke multiple cardiac arrhythmia syndromes by influencing diverse components of Na(+) channel gating function. The full text of this article is available at http://www.circresaha.org. Key Words: Na(+) channel inactivation long-QT syndrome Brugada syndrome
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PMID:UltraRapid communications : vascular superoxide production by NAD(P)H OxidaseAssociation with endothelial dysfunction and clinical risk factors 1080 75

Superoxide anion plays important roles in vascular disease states. Increased superoxide production contributes to reduced nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of vascular disease. We measured superoxide production by NAD(P)H oxidase in human blood vessels and examined the relationships between NAD(P)H oxidase activity, NO-mediated endothelial function, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations and direct measurements of vascular superoxide production were determined in human saphenous veins obtained from 133 patients with coronary artery disease and identified risk factors. The predominant source of vascular superoxide production was an NAD(P)H-dependent oxidase. Increased vascular NAD(P)H oxidase activity was associated with reduced NO-mediated vasorelaxation. Furthermore, reduced endothelial vasorelaxations and increased vascular NAD(P)H oxidase activity were both associated with increased clinical risk factors for atherosclerosis. Diabetes and hypercholesterolemia were independently associated with increased NADH-dependent superoxide production. The association of increased vascular NAD(P)H oxidase activity with endothelial dysfunction and with clinical risk factors suggests an important role for NAD(P)H oxidase-mediated superoxide production in human atherosclerosis. The full text of this article is available at http://www.circresaha.org.
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PMID:Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. 1080 76

Angiotensin II (ANG II) has multiple effects on cardiovascular and renal cells, including vasoconstriction, cell growth, induction of proinflammatory cytokines, and profibrogenic actions. Recent studies provide evidence that ANG II could stimulate intracellular formation of reactive oxygen species (ROS) such as the superoxide anion (O2-). This ANG II-mediated ROS formation exhibits different kinetic and lower absolute concentrations than those traditionally observed during the respiratory burst of phagocytic cells, but it likely involves similar membrane-bound NAD(P)H-oxidases. Current evidence suggests that ANG II, through AT1-receptor activation, upregulates several subunits of this multienzyme complex, resulting in an increase in intracellular O2- concentration. ROS are involved in several signal pathways, and redox-sensitive transcriptional factors (AP-1, NF-kappaB) have been characterized. ANG II-induced ROS play a pivotal role in several pathophysiologic situations of vascular and renal cells such as hypertension, endothelial dysfunction, nitrate tolerance, atherosclerosis, and cellular remodeling. Although these perceptions suggest that drugs interfering with ANG II effects (ACE inhibitors, AT1 -receptor antagonist) may serve as antioxidants, preventing vascular and renal changes, the clinical studies are not so straightforward. In fact, only specific risk groups, such as patients with diabetes mellitus or renal insufficiency, may benefit from ACE inhibitors, whereas hard endpoints showed no advantage for ACE inhibitors in patients with essential hypertension.
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PMID:Free radical production and angiotensin. 1098 Nov 45

Elevated plasma levels of the sulfur-containing amino acid homocysteine increase the risk for atherosclerosis, stroke, and possibly Alzheimer's disease, but the underlying mechanisms are unknown. We now report that homocysteine induces apoptosis in rat hippocampal neurons. DNA strand breaks and associated activation of poly-ADP-ribose polymerase (PARP) and NAD depletion occur rapidly after exposure to homocysteine and precede mitochondrial dysfunction, oxidative stress, and caspase activation. The PARP inhibitor 3-aminobenzamide (3AB) protects neurons against homocysteine-induced NAD depletion, loss of mitochondrial transmembrane potential, and cell death, demonstrating a requirement for PARP activation and/or NAD depletion in homocysteine-induced apoptosis. Caspase inhibition accelerates the loss of mitochondrial potential and shifts the mode of cell death to necrosis; inhibition of PARP with 3AB attenuates this effect of caspase inhibition. Homocysteine markedly increases the vulnerability of hippocampal neurons to excitotoxic and oxidative injury in cell culture and in vivo, suggesting a mechanism by which homocysteine may contribute to the pathogenesis of neurodegenerative disorders.
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PMID:Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. 1099 36

Emerging evidence indicates that reactive oxygen species, especially superoxide and hydrogen peroxide, are important signaling molecules in cardiovascular cells. Their production is regulated by hormone-sensitive enzymes such as the vascular NAD(P)H oxidases, and their metabolism is coordinated by antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Both of these reactive oxygen species serve as second messengers to activate multiple intracellular proteins and enzymes, including the epidermal growth factor receptor, c-Src, p38 mitogen-activated protein kinase, Ras, and Akt/protein kinase B. Activation of these signaling cascades and redox-sensitive transcription factors leads to induction of many genes with important functional roles in the physiology and pathophysiology of vascular cells. Thus, reactive oxygen species participate in vascular smooth muscle cell growth and migration; modulation of endothelial function, including endothelium-dependent relaxation and expression of a proinflammatory phenotype; and modification of the extracellular matrix. All of these events play important roles in vascular diseases such as hypertension and atherosclerosis, suggesting that the sources of reactive oxygen species and the signaling pathways that they modify may represent important therapeutic targets.
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PMID:Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. 1103 Dec 1

ADVERSE EFFECTS OF OXYGEN: Adverse effect of oxygen on anaerobes implies oxidation of the basic cell constituents NAD(P)H, thiols, iron-sulphur proteins, pteridines and others) and inactivation of the essential components of the active site of enzymes. Oxygen can also adversely affect the aerobes, especially if long-term influence is taken into consideration, while exposition to high-pressure oxygen causes considerable damages. Direct influence of oxygen on aerobes due to slow and limited enzyme inactivation (for example glutamate decarboxylase) and small number of affected "targets" is not responsible for total adverse effects of oxygen. Even in 1954 it was supposed that oxygen free radicals are the most responsible for the adverse effects of oxygen. ATMOSPHERIC (TRIPLET) OXYGEN: Electron configuration of triplet oxygen explains its reactivity since it is a biradical. The reactions of oxygen with non-radicals are possible with participation of transition metals (except zinc), while its reactivity is much more expressed in case of reactions with other radical species. ACTIVE OXYGEN: More reactive forms of oxygen, known as singlet oxygen, can be generated by an input of energy to triplet oxygen. Singlet-oxygen is obtained mainly by photoexcitation in the presence of initiators (methylene blue, chlorophyll etc.) and as a product of reactions of ozone with certain biomolecules. REDUCED FORMS OF OXYGEN: If a single electron is added to the triplet oxygen, it must enter one of the antibonding molecular orbitals and produce the superoxide radical--(O2.-). Addition of one more electron produces peroxide ion--O2(2-), which forms hydro peroxide in presence of H+, the most common two-electron reduction product of oxygen in biological systems. The four-reduction product of oxygen in biological systems is water. SUPEROXIDE RADICAL: The in vivo production of superoxide radical is possible in many different ways mentioned in this paper. This radical species is unstable in water solutions because of dismutation reaction leading to non-enzymic generation of hydroperoxide. The most reactive radical species--hydroxyl radical is produced from hydro peroxide by Fenton or Haber-Weiss reactions in the presence of catalytic transition metals (iron or copper). HYDROXYL RADICAL: Hydroxyl radicals are the most reactive radical species. The way of their generation has been shown in detail in this paper with special emphasis given to Fenton and Haber-Weiss reactions, that is, transition metals (iron and copper) as catalizators for these reactions. The reactivity of hydroxyl radical can be recognized by monitoring the second-order rate constants for reactions of the hydroxyl radical with some organic compounds in aqueous solution presented in this paper. Although the number of compounds that can be affected and damaged by hydroxyl radicals is great, until now, attention has been paid mostly to investigation of attacks of these radical species on lipids, proteins and DNA. LIPID PEROXIDATION: Radicals react with lipids and cause oxidative destruction of unsaturated, that is, polyunsaturated fatty acids, known as lipid peroxidation. Both lipids in biological systems and lipids as food constituents are submitted to this process. Lipid peroxidation is a chain reaction and its mechanism has been shown in detail in this paper. Lipid peroxidation in cells leads to direct damage of cell membranes with indirect damages of other cell constituents, caused by reactivity of secondary products of this reaction, aldehydes. This complex reaction is responsible for damages of many tissues and progress of some diseases (atherosclerosis). OXIDATIVE STRESS: Protection of an organism from oxygen free radicals implies activity of enzymatic (catalase, SOD, glutathione peroxidase, glutathione reductase etc.) and nonenzymatic (vitamin E. vitamin C. glutathione, uric acid etc.) systems of protection. Disturbance of the balance between production of oxygen free radicals (or some other radical species) and activity of antioxidative system of protection causes the so called oxidative stress. An organism can tolerate a mild oxidative stress but a higher disturbance between the production of free radicals and the activity of the antioxidative protection results in lipid protein and DNA as well as numerous diseases.
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PMID:[Free oxygen radiacals and kidney diseases--part I]. 1132 Jul 27

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.
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PMID:NAD(P)H, a directly operating antioxidant? 1142 89

Vascular endothelial cells are constantly subjected to pressure-induced cyclic strain. Reactive oxygen species (ROS) have been implicated in atherosclerosis and vascular remodeling. Recent evidence indicates that a vascular NAD(P)H oxidase may be an important source of ROS in both physiologic and pathophysiologic situations. The aim of this study was to investigate cyclic strain-induced NAD(P)H oxidase activity in endothelial cells. ROS production was examined by electron paramagnetic resonance and lucigenin chemiluminescence. Cyclic strain-induced NAD(P)H oxidase activity was quantified by activity assay while the expression of p22phox was monitored by Northern blotting. Endothelial cells produce basal amounts of ROS that were enhanced by cyclic strain. Moreover subsequent stimulation with TNF-alpha resulted in significantly greater ROS production in cells previously exposed to cyclic strain as compared to static conditions. Cyclic strain resulted in a significant increase in message for the p22phox subunit as well as activity of the NAD(P)H oxidase. The induced oxidative stress was accompanied by increased mobilization of the transcription factor NFkappaB, an effect that was blocked by a pharmacological inhibitor of NAD(P)H. These results demonstrate a pivotal role for NAD(P)H oxidase in cyclic strain-induced endothelial ROS production and may provide insight into the modulation of vascular disease by biomechanical forces. J. Cell. Biochem. Suppl. 36: 99-106, 2001.
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PMID:Cyclic strain induces reactive oxygen species production via an endothelial NAD(P)H oxidase. 1145 75

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