Electron Spin Resonance Characterization of Vascular Xanthine and NAD(P)H Oxidase Activity in Patients With Coronary Artery Disease

Spiekermann, Stephan; Landmesser, Ulf; Dikalov, Sergey; Bredt, Martin; Gamez, Graciela; Tatge, Helma; Reepschläger, Nina; Hornig, Burkhard; Drexler, Helmut; Harrison, David G.

doi:10.1161/01.cir.0000056762.69302.46

Cited by 268 publications

(182 citation statements)

References 44 publications

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“…FID was reduced in the presence of KCl in CAD patients, implicating potassium channel activation. Similar to previous studies showing increased ROS generation in patients with CAD (33,50), flow-induced generation of H 2 O 2 and superoxide fluorescence increased in adipose arterioles in patients with CAD more than in control patients without CAD. The effect of catalase on reducing H 2 O 2 production confirms specificity of the DCFH fluorescence (17,38).…”

Section: H97 Human Adipose Circulation and Mechanisms Of Fidsupporting

confidence: 89%

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The mechanism of flow-induced dilation in human adipose arterioles involves hydrogen peroxide during CAD

Phillips

Hatoum

Gutterman

2007

American Journal of Physiology-Heart and Circulatory Physiology

106

116

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Phillips SA, Hatoum OA, Gutterman DD. The mechanism of flowinduced dilation in human adipose arterioles involves hydrogen peroxide during CAD. Am J Physiol Heart Circ Physiol 292: H93-H100, 2007. First published October 13, 2006; doi:10.1152/ajpheart.00819.2006 is an important physiological stimulus that regulates tissue blood flow and is mediated by endotheliumderived factors that play a role in vascular integrity and the development of atherosclerosis. In coronary artery disease (CAD), conduit artery FID is impaired. The purpose of this study was to determine the mechanism of FID in human visceral adipose and examine whether the presence of conduit coronary atherosclerosis is associated with altered endothelial function in visceral fat. FID was determined in isolated visceral fat arterioles from patients with and without CAD. After constriction with endothelin-1, increases in flow produced an endothelium-dependent vasodilation that was sensitive to N -nitro-Larginine methyl ester (L-NAME) in visceral fat arterioles from patients without CAD. In contrast, L-NAME alone or in combination with indomethacin had no effect on FID in similarly located arterioles from patients with CAD. Flow increased dichlorofluorescein (DCF) and dihydroethidium fluorescence accumulation in arterioles from patients with CAD versus without, indicative of the production of oxidative metabolites and superoxide, respectively. Both the dilation and DCF fluorescence to flow were reduced in the presence of the H 2O2 scavenger polyethylene glycol-catalase. Exogenous H2O2 elicited similar relaxations of arterioles from patients in both groups. These data indicate that FID in visceral fat arterioles is nitric oxide dependent in the absence of known CAD. However, in the presence of CAD, H 2O2 replaces nitric oxide as the mediator of endotheliumdependent FID. This study provides evidence that adverse microvascular changes during CAD are evident in human visceral adipose, a tissue associated with CAD. coronary artery disease; blood flow; vasodilation; microcirculation FLOW-INDUCED DILATION (FID) is a physiologically important stimulus regulating vascular tone and homeostasis of the peripheral circulation. This important endothelial mechanism of vasodilation occurs in virtually every vascular bed and, in large arteries, may be critical for preventing atherosclerosis through release of the endothelium-derived antiproliferative compounds nitric oxide (NO) and prostacyclin (PGI 2 ) (21,25,39,51). Many of the studies implicating the role of NO (24) and PGI 2 (26) in FID have been performed in animal models in the absence of coronary artery disease (CAD). However, no studies have evaluated the mechanism of FID in isolated human microvessels from human visceral adipose with or without CAD. Human adipose has been proposed as a source for endocrine and paracrine modulation of vascular function during the establishment of atherosclerosis, and therefore vessels in this region could serve as sentinels for endothelial alterations produced by the proatheroscler...

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Section: H97 Human Adipose Circulation and Mechanisms Of Fidsupporting

confidence: 89%

“…Previous studies implicate NADPH oxidase as the major source of ROS during atherosclerosis (37,50). Other likely contributors to ROS production during CAD are mitochondria, CYP-450, xanthine oxidase, and lipoxygenase and should be examined in future studies.…”

Section: H97 Human Adipose Circulation and Mechanisms Of Fidmentioning

confidence: 97%

The mechanism of flow-induced dilation in human adipose arterioles involves hydrogen peroxide during CAD

Phillips

Hatoum

Gutterman

2007

American Journal of Physiology-Heart and Circulatory Physiology

106

116

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“…ROS production in MP-treated endothelial cells was enhanced in the presence of the PI3K inhibitor, but was not influenced by MEK blockade, giving evidence that the PI3K, but not the ERK 1/2, pathway partially and negatively regulates ROS generation. Among the main sources of ROS, NADPH and xanthine oxidases play a major role in vascular cells (41), although eNOS and complex I in mitochondria can also be involved in ROS production. Here, we showed that among the pharmacological inhibitors used, inhibition of xanthine oxidase reduced the ability of MPs to produce ROS.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 3-Kinase and Xanthine Oxidase Regulate Nitric Oxide and Reactive Oxygen Species Productions by Apoptotic Lymphocyte Microparticles in Endothelial Cells

Mostefai

Agouni

Carusio

et al. 2008

The Journal of Immunology

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Microparticles (MPs) are membrane vesicles released during cell activation and apoptosis. We have previously shown that MPs from apoptotic T cells induce endothelial dysfunction, but the mechanisms implicated are not completely elucidated. In this study, we dissect the pathways involved in endothelial cells with respect to both NO and reactive oxygen species (ROS). Incubation of endothelial cells with MPs decreased NO production that was associated with overexpression and phosphorylation of endothelial NO synthase (eNOS). Also, MPs enhanced expression of caveolin-1 and decreased its phosphorylation. Microparticles enhanced ROS by a mechanism sensitive to xanthine oxidase and P-IκBα inhibitors. PI3K inhibition reduced the effects of MPs on eNOS, but not on caveolin-1, whereas it enhanced the effects of MPs on ROS production. Microparticles stimulated ERK1/2 phosphorylation via a PI3K-depedent mechanism. Inhibition of MEK reversed eNOS phosphorylation but had no effect on ROS production induced by MPs. In vivo injection of MPs in mice impaired endothelial function. In summary, MPs activate pathways related to NO and ROS productions through PI3K, xanthine oxidase, and NF-κB pathways. These data underscore the pleiotropic effects of MPs on NO and ROS, leading to an increase oxidative stress that may account for the deleterious effects of MPs on endothelial function.

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“…XOR as a nitrite reductase is of particular interest because its activity and expression is elevated in models of atherosclerosis (50) and in human disease within plaques (51), as well as the peripheral endothelium (52). The main source of XOR is the liver from where it is shed into the circulation during periods of stress (53) and then binds with high affinity to endothelial cells via glycosaminoglycans (54).…”

Section: (B) the Same Pattern Was Observed In Erythrocytes (G And H)mentioning

confidence: 99%

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

Khambata

Ghosh

Rathod

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Reduced bioavailable nitric oxide (NO) plays a key role in the enhanced leukocyte recruitment reflective of systemic inflammation thought to precede and underlie atherosclerotic plaque formation and instability. Recent evidence demonstrates that inorganic nitrate (NO 3 − ) through sequential chemical reduction in vivo provides a source of NO that exerts beneficial effects upon the cardiovascular system, including reductions in inflammatory responses. We tested whether the antiinflammatory effects of inorganic nitrate might prove useful in ameliorating atherosclerotic disease in Apolipoprotein (Apo)E knockout (KO) mice. We show that dietary nitrate treatment, although having no effect upon total plaque area, caused a reduction in macrophage accumulation and an elevation in smooth muscle accumulation within atherosclerotic plaques of ApoE KO mice, suggesting plaque stabilization. We also show that in nitratefed mice there is reduced systemic leukocyte rolling and adherence, circulating neutrophil numbers, neutrophil CD11b expression, and myeloperoxidase activity compared with wild-type littermates. Moreover, we show in both the ApoE KO mice and using an acute model of inflammation that this effect upon neutrophils results in consequent reductions in inflammatory monocyte expression that is associated with elevations of the antiinflammatory cytokine interleukin (IL)-10. In summary, we demonstrate that inorganic nitrate suppresses acute and chronic inflammation by targeting neutrophil recruitment and that this effect, at least in part, results in consequent reductions in the inflammatory status of atheromatous plaque, and suggest that this effect may have clinical utility in the prophylaxis of inflammatory atherosclerotic disease.

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Electron Spin Resonance Characterization of Vascular Xanthine and NAD(P)H Oxidase Activity in Patients With Coronary Artery Disease

Cited by 268 publications

References 44 publications

The mechanism of flow-induced dilation in human adipose arterioles involves hydrogen peroxide during CAD

The mechanism of flow-induced dilation in human adipose arterioles involves hydrogen peroxide during CAD

Phosphatidylinositol 3-Kinase and Xanthine Oxidase Regulate Nitric Oxide and Reactive Oxygen Species Productions by Apoptotic Lymphocyte Microparticles in Endothelial Cells

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

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