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

The NAD(P)H oxidase is an enzyme assembled at the cellular membrane able to produce superoxide anion from NADH or NAD(P)H (nicotinamide adenine dinucleotide phosphate). It is one of the main sources of superoxide anion in cardiovascular tissues and its role in a variety of cardiovascular disorders such as atherosclerosis, cardiac hypertrophy, and endothelial dysfunction was recently proposed. Although, many factors and receptors were shown to lead to the activation of the enzyme, particulary the type 1 angiotensin receptor, the pathways involved are still widely unknown. Despite the identification of factors such as c-Src and protein kinase C implicated in the acute activation of NAD(P)H oxidase, the signalling involved in the sustained activation of the enzyme is probably far more complex than was previously envisioned. In this review, we describe the role of endothelin-1 in NAD(P)H oxidase signalling after a sustained stimulation by angiotensin II. Since most pathologies caused by an NAD(P)H oxidase overactivation develop over a relatively long period of time, it is necessary to better understand the long-term signalling of the enzyme for the development or use of more specific therapeutic tools.
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PMID:The interrelation of the angiotensin and endothelin systems on the modulation of NAD(P)H oxidase. 1684 87

Renal artery stenosis (RAS) is usually observed in hypertensive patients with extensive atherosclerosis. There is some evidence that in these patients the atherosclerotic process and the consequent target-organ damage is more severe than in hypertensive patients without RAS. In this review we will entertain the hypothesis that some of the humoral factors that are activated by RAS may contribute to accelerate the progression of atherosclerosis. Several studies identified RAS as a predictor of cardiovascular events in high-risk patients, although in most cases the contribution of blood pressure per se to the progression of vascular lesions could not be determined. As a result of experimental RAS, hypertension and increased oxidative stress are stimuli for atherosclerosis as well as cardiac and renal damage. In the presence of RAS, the renin-angiotensin system is stimulated, and it has been shown that angiotensin II exerts proinflammatory, pro-oxidant and procoagulant activities in experimental models and humans. The potential contribution of reactive oxygen species to the prohypertensive and proatherosclerotic effects of RAS is supported by evidence that nicotinamide adenine dinucleotide phosphate, reduced form oxidase is specifically stimulated by angiotensin II, an activity not shared by epinephrine. Moreover, angiotensin II triggers the release of aldosterone, endothelin 1, thromboxane A2 and other derivatives of the arachidonic acid metabolism, all of which can further and independently aggravate cardiovascular damage. Epidemiological and experimental evidence so far available suggests that accelerated atherosclerosis can be both the cause and the consequence of RAS.
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PMID:Renal artery stenosis and accelerated atherosclerosis: which comes first? 1691 13

Hypertension is a well-known risk factor for atherosclerosis, but the molecular mechanisms that link elevated blood pressure to the progression of atherosclerosis remain unclear. Human urotensin II (U-II), the most potent endogenous vasoconstrictor peptide identified to date, and its receptor (UT receptor) are involved in the etiology of essential hypertension. In patients with essential hypertension, U-II infused into the forearm brachial artery has been shown to induce vasoconstriction. Recent studies have demonstrated elevated plasma U-II concentrations in patients with essential hypertension, diabetes mellitus, atherosclerosis, and coronary artery disease. U-II is expressed in endothelial cells, macrophages, macrophage-derived foam cells, and myointimal and medial vascular smooth muscle cells (VSMCs) of atherosclerotic human coronary arteries. UT receptors are present in VSMCs of human coronary arteries, the thoracic aorta and cardiac myocytes. Lymphocytes are the most active producers of U-II, whereas monocytes and macrophages are the major cell types expressing UT receptors, with relatively little receptor expression in foam cells, lymphocytes, and platelets. U-II accelerates foam cell formation by up-regulation of acyl-coenzyme A:cholesterol acyltransferase-1 in human monocyte-derived macrophages. In human endothelial cells, U-II promotes cell proliferation and up-regulates type 1 collagen expression. U-II also activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and plasminogen activator inhibitor-1 in human VSMCs, and stimulates VSMC proliferation with synergistic effects observed when combined with oxidized low-density lipoprotein, lysophosphatidylcholine, reactive oxygen species or serotonin. These findings suggest that U-II plays key roles in accelerating the development of atherosclerosis, thereby leading to coronary artery disease.
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PMID:Human urotensin II as a link between hypertension and coronary artery disease. 1694 Jun 99

We examined whether amlodipine, an L-type calcium channel blocker (CCB), has an inhibitory effect on oxidative stress and inflammatory response, and thereby atherosclerosis, in apolipoprotein E-deficient (ApoEKO) mice. Adult male ApoEKO mice (6 weeks of age) were fed a high-cholesterol diet (HCD) for 8 or 10 weeks with or without oral administration of amlodipine (3 mg/kg/day) for 10 weeks or for only the last 2 weeks of the HCD. After HCD feeding, atherosclerotic lesion formation, in situ superoxide production and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity were evaluated in the proximal aorta. The expressions of NADPH oxidase subunits (p47(phox) and rac-1), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were determined with immunohistochemistry and quantitative real-time reverse-transcription polymerase chain reaction. After 8 to 10 weeks of HCD administration to ApoEKO mice, marked atherosclerotic lesion formation was observed in the proximal aorta. In the atherosclerotic lesion, superoxide production, the expression of NADPH oxidase subunits, and NADPH oxidase activity were enhanced, and the expressions of MCP-1, ICAM-1, and VCAM-1 were increased. These changes were suppressed in mice that were treated with amlodipine for 10 weeks concomitant with HCD administration, with no significant change in blood pressure and plasma cholesterol level. We also observed that treatment with amlodipine for only the last 2 weeks regressed the atherosclerotic lesions with a decrease in oxidative stress and vascular inflammation. Inhibition of the atherosclerotic lesion area and lipid area in the proximal aorta by amlodipine was correlated with its inhibitory actions on oxidative stress, inflammation and the production of adhesive molecules. These results suggest that amlodipine not only inhibits atherosclerotic lesion formation, but also regresses atherosclerosis, and that these effects are at least partly due to inhibition of oxidative stress and inflammatory response.
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PMID:Regression of atherosclerosis by amlodipine via anti-inflammatory and anti-oxidative stress actions. 1694 Jul 9

Nicotinic acid is a safe, broad-spectrum lipid agent shown to prevent cardiovascular disease, yet its widespread use is limited by the prostaglandin D2 (PGD2) mediated niacin flush. Previous research suggests that nicotinic acid-induced PGD2 secretion is mediated by the skin, but the exact cell type remains unclear. We hypothesized that macrophages are a source of nicotinic acid-induced PGD2 secretion and performed a series of experiments to confirm this. Nicotinic acid (0.1-3 mM) induced PGD2 secretion in cultured human macrophages, but not monocytes or endothelial cells. The PGD2 secretion was dependent on the concentration of nicotinic acid and the time of exposure. Nicotinuric acid, but not nicotinamide, also induced PGD2 secretion. Pre-incubation of the cells with aspirin (100 microM) entirely prevented the nicotinic acid effects on PGD2 secretion. The PGD2 secreting effects of nicotinic acid were additive to the effects of the calcium ionophore A23187 (6 microM), but were independent of extra cellular calcium. These findings, combined with recent in vivo work, provide evidence that macrophages play a significant role in mediating the niacin flush and may lead to better strategies to eliminate this limiting side effect.
Atherosclerosis 2007 Jun
PMID:Nicotinic acid induces secretion of prostaglandin D2 in human macrophages: an in vitro model of the niacin flush. 1694 75

Angiotensin II (Ang II) increases adhesion molecules, cytokines and chemokines and exerts a proinflammatory effect on leucocytes, endothelial cells and vascular smooth muscle cells. Acting via the type 1 receptor, Ang II initiates an inflammatory cascade of reduced nicotinamide-adenine dinucleotide phosphate oxidase, reactive oxygen species (ROS) and nuclear factor-kappaB, which mediates transcription and gene expression and increases adhesion molecules and chemokines. An excess of ROS decreases nitric oxide bioavailability, causes endothelial dysfunction, and promotes atherosclerosis. Moreover, Ang II interrupts the anti-inflammatory effects of insulin. Together, these effects promote a prothrombotic state as well as plaque rupture. Ang II receptor blockers suppress mediators of inflammation, including ROS and C-reactive protein, and they increase expression of inhibitory kappaB (an inhibitor of nuclear factor-kappaB). These anti-inflammatory and antioxidative effects, which are probably due in part to unopposed stimulation of the Ang II type 2 receptor, may be beneficial in acute coronary syndromes and may also contribute to the prevention of type II diabetes mellitus, as insulin resistance is mediated by inflammatory processes.
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PMID:Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. 1709 9

Chronic oxidative stress that characterizes uremia has potentially devastating effects on the vasculature and has been advocated in the pathogenesis of accelerated atherosclerosis in this disease. Recent advances have been made in our understanding of the molecular mechanisms that regulate expression and activity of key enzymes of vascular oxidative stress (eg, nicotinamide adenine dinucleotide phosphate [NAD{P}H] oxidase) and that dissect their interactions with signalling pathways of inflammation. The finding that NAD(P)H oxidase is upregulated in experimental uremia has important consequences from a physiologic and a therapeutic standpoint. In addition, identification of novel proteins involved in systemic oxidative stress has shed some new light on the pathogenesis of vascular disease. p66(shc) is a cytoplasmic protein that is expressed in a wide range of cell types. Initially believed to be involved in signalling pathways that regulate cell growth and oxidative stress, it has now been shown to play a pivotal role in promoting endothelial dysfunction and atherosclerosis. Although a specific role in uremia-related vascular disease has not yet been shown, available data in humans suggest involvement of p66(shc) in clinical conditions associated with increased oxidative stress.
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PMID:Vascular sources of oxidative stress: implications for uremia-related cardiovascular disease. 1719 33

In the present study, the effect of succinic acid monoethyl ester (EMS) on the pattern of lipids and lipoproteins in streptozotocin-nicotinamide induced type 2 diabetes was investigated. Type 2 diabetes was induced in male Wistar rats by single intraperitoneal injection (i.p.) of 45 mg/kg streptozotocin, 15 min after the i.p administration of 110 mg/kg body weight of nicotinamide. The carboxylic nutrient EMS was administered intraperitonially at a dose of 8 micromol/g body weight for 30 days. At the end of experimental period, the effect of EMS on plasma glucose, insulin, thiobarbituric acid reactive substances (TBARS) and hydroperoxide (HP) and serum triglycerides (TG), phospholipids (PL), free fatty acids (FFA), total cholesterol (TC), very low density lipoprotein-cholesterol (VLDL-C) and low density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and the percentage of antiatherogenic index (AAI) (ratio of HDL-C to total cholesterol) were studied. Administration of EMS to diabetic rats resulted in a significant reduction in the elevated levels of plasma glucose, TBARS and hydroperoxides as well as TG, PL, FFA, TC,VLDL-C and LDC-C levels. The decreased plasma insulin and serum HDL-C and percentage of AAI in diabetic rats were also reversed towards near normal. The effect produced by EMS was compared with metformin, a reference drug. The results indicates that the administration of EMS and metformin to nicotinamide-streptozotocin diabetic rats normalized plasma glucose, insulin concentrations and caused marked improvement in altered lipids, lipoprotein and lipid peroxidation markers during diabetes. Our results show the antihyperlipidemic properties of EMS and metformin in addition to its antidiabetic action. Moreover, the antihyperlipidemic effect could represent a protective mechanism against the development of atherosclerosis.
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PMID:Effect of a novel insulinotropic agent, succinic acid monoethyl ester, on lipids and lipoproteins levels in rats with streptozotocin-nicotinamide-induced type 2 diabetes. 1730 96

Extending the productive lifespan of human cells could have major implications for diseases of aging, such as atherosclerosis. We identified a relationship between aging of human vascular smooth muscle cells (SMCs) and nicotinamide phosphoribosyltransferase (Nampt/PBEF/Visfatin), the rate-limiting enzyme for NAD+ salvage from nicotinamide. Replicative senescence of SMCs was preceded by a marked decline in the expression and activity of Nampt. Furthermore, reducing Nampt activity with the antagonist FK866 induced premature senescence in SMCs, assessed by serial quantification of the proportion of cells with senescence-associated beta-galactosidase activity. In contrast, introducing the Nampt gene into aging human SMCs delayed senescence and substantially lengthened cell lifespan, together with enhanced resistance to oxidative stress. Nampt-mediated SMC lifespan extension was associated with increased activity of the NAD+-dependent longevity enzyme SIRT1 and was abrogated in Nampt-overexpressing cells transduced with a dominant-negative form of SIRT1 (H363Y). Nampt overexpression also reduced the fraction of p53 that was acetylated on lysine 382, a target of SIRT1, suppressed an age-related increase in p53 expression, and increased the rate of p53 degradation. Moreover, add-back of p53 with recombinant adenovirus blocked the anti-aging effects of Nampt. These data indicate that Nampt is a longevity protein that can add stress-resistant life to human SMCs by optimizing SIRT1-mediated p53 degradation.
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PMID:Extension of human cell lifespan by nicotinamide phosphoribosyltransferase. 1730 30

Low ethanol intake is known to have a beneficial effect on cardiovascular disease. In cardiovascular disease, insulin resistance leads to altered glucose and lipid metabolism resulting in an increased production of aldehydes, including methylglyoxal. Aldehydes react non-enzymatically with sulfhydryl and amino groups of proteins forming advanced glycation end products (AGEs), altering protein structure and function. These alterations cause endothelial dysfunction with increased cytosolic free calcium, peripheral vascular resistance, and blood pressure. AGEs produce atherogenic effects including oxidative stress, platelet adhesion, inflammation, smooth muscle cell proliferation and modification of lipoproteins. Low ethanol intake attenuates hypertension and atherosclerosis but the mechanism of this effect is not clear. Ethanol at low concentrations is metabolized by low Km alcohol dehydrogenase and aldehyde dehydrogenase, both reactions resulting in the production of reduced nicotinamide adenine dinucleotide (NADH). This creates a reductive environment, decreasing oxidative stress and secondary production of aldehydes through lipid peroxidation. NADH may also increase the tissue levels of the antioxidants cysteine and glutathione, which bind aldehydes and stimulate methylglyoxal catabolism. Low ethanol improves insulin resistance, increases high-density lipoprotein and stimulates activity of the antioxidant enzyme, paraoxonase. In conclusion, we suggest that chronic low ethanol intake confers its beneficial effect mainly through its ability to increase antioxidant capacity and lower AGEs.
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PMID:Beneficial effect of low ethanol intake on the cardiovascular system: possible biochemical mechanisms. 1732 32


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