Role of NADPH Oxidase in Endothelial Ischemia/Reperfusion Injury in Humans

Loukogeorgakis, Stavros; M, van den Berg; Sofat, Reecha; Nitsch, Dorothea; Charakida, Marietta; Haiyee, Bu’Hussein; Groot, Eric de; MacAllister, Raymond J.; Kuijpers, Taco W.; Deanfield, John

doi:10.1161/circulationaha.108.814731

Cited by 95 publications

(70 citation statements)

References 67 publications

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“…NOX2 deficiency causes X-linked granulomatous disease. Normal human subjects all experienced impairment of flow-mediated dilation after 20 min of arm ischemia while patients with NOX2 deficiency (or p47 phox deficiency) did not (1079), again demonstrating relevance of NOX2 in short-term endothelial function. Endothelial NOX5 expression was sevenfold higher in early human coronary atherosclerotic lesions and contributes to ROS production (680).…”

Section: Signaling Cassettes Activated By Rtk Are Mutually Supportivementioning

confidence: 92%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

389

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Section: Signaling Cassettes Activated By Rtk Are Mutually Supportivementioning

confidence: 92%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

389

344

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“…However, a series of studies by Viola and colleagues, in which patients with Nox deficiency (chronic granulomatous disease) were studied, demonstrated that Noxs and ROS are important in the regulation of vascular tone (122,124,225). This was evidenced by the following: patients with Nox 2 or p47phox deficiency had significantly higher forearm-mediated dilation and lower serum levels of soluble Nox2-derived peptide (marker of Nox2 activation) and 8-iso-PGF2a levels compared with healthy subjects; platelets from patients with Nox2 deficiency have reduced isoprostane formation; patients with CGD are protected from ischemia-reperfusion injury (121,122,124,225). Moreover, women carriers of hereditary deficiency of Nox2 had higher flow-mediated dilation, lower intima-media thickness, reduced urinary isoprostanes and serum Nox2 activity, increased NO bioavailability, and higher serum nitrite/ nitrate compared with controls, suggesting reduced vascular damage and atherosclerotic burden in carriers of Nox2 deficiency (224).…”

Section: Ros Noxs and Vascular Function: Clues From Studies In Patimentioning

confidence: 99%

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

Montezano

Touyz²

2014

Antioxidants & Redox Signaling

236

177

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Significance: Reactive oxygen species (ROS) are signaling molecules that are important in physiological processes, including host defense, aging, and cellular homeostasis. Increased ROS bioavailability and altered redox signaling (oxidative stress) have been implicated in the onset and/or progression of chronic diseases, including hypertension. Recent Advances: Although oxidative stress may not be the only cause of hypertension, it amplifies blood pressure elevation in the presence of other pro-hypertensive factors, such as salt loading, activation of the renin-angiotensin-aldosterone system, and sympathetic hyperactivity, at least in experimental models. A major source for ROS in the cardiovascular-renal system is a family of nicotinamide adenine dinucleotide phosphate oxidases (Noxs), including the prototypic Nox2-based Nox, and Nox family members: Nox1, Nox4, and Nox5. Critical Issues: Although extensive experimental data support a role for increased ROS levels and altered redox signaling in the pathogenesis of hypertension, the role in clinical hypertension is unclear, as a direct causative role of ROS in blood pressure elevation has yet to be demonstrated in humans. Nevertheless, what is becoming increasingly evident is that abnormal ROS regulation and aberrant signaling through redoxsensitive pathways are important in the pathophysiological processes which is associated with vascular injury and target-organ damage in hypertension. Future Directions: There is a paucity of clinical information related to the mechanisms of oxidative stress and blood pressure elevation, and a few assays accurately measure ROS directly in patients. Such further ROS research is needed in humans and in the development of adequately validated analytical methods to accurately assess oxidative stress in the clinic. Antioxid. Redox Signal. 20,[164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182]

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“…One novel approach is the study of patients with polymorphisms or mutations of genes that might play a pathogenic role. [47][48][49][50] Such studies provide a human parallel for knockout mouse studies. For example, Antoniades and colleagues 47 examined how homocysteine metabolism may affect the endothelium and promote cardiovascular disease.…”

Section: Mechanisms Of Endothelial Dysfunction: Human Studiesmentioning

confidence: 99%

“…Using the same approach, 2 groups of investigators examined mutations in genes for subunits of NADPH oxidase and the consequences for endothelial function in humans. 48,49 Chronic granulomatous disease is an inherited condition caused by detects in NADPH oxidase that lead to impaired immune function and chronic susceptibility to infection. NAPDH oxidase has also been implicated in experimental studies to be a major source of reactive oxygen species that contributes to endothelial dysfunction in a variety of disease states, including diabetes mellitus, hypertension, and ischemia reperfusion injury.…”

Section: Mechanisms Of Endothelial Dysfunction: Human Studiesmentioning

confidence: 99%

Endothelial Function

2011

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T he endothelium regulates vascular tone, platelet activity, leukocyte adhesion, and angiogenesis by producing nitric oxide and other regulatory factors. Risk factors decrease nitric oxide bioavailability and induce a proinflammatory endothelial phenotype that promotes atherosclerosis. 1,2 In human subjects, endothelial dysfunction is associated with risk factors, [3][4][5] correlates with disease progression, 6 and predicts cardiovascular events. [7][8][9][10][11][12][13] Risk reduction therapies improve endothelial function, and failure of the endothelium to respond is associated with higher risk. 14 Thus, there is strong clinical evidence that endothelial dysfunction contributes to the pathogenesis of cardiovascular disease.In the past several years, experimental and clinical studies have provided new information about the mechanisms and clinical relevance of specific aspects of endothelial function. The purpose of this review is to summarize recent articles from Circulation that have advanced this field. Mechanisms of Endothelial Dysfunction: Experimental ModelsLoss of nitric oxide bioavailability (decreased synthesis or increased degradation) is a key manifestation of endothelial dysfunction that contributes to the pathogenesis and clinical expression of atherosclerosis. Endogenous inhibitors of endothelial nitric oxide synthase (eNOS), including asymmetrical dimethyl arginine, are elevated, and contribute to endothelial dysfunction in diabetes mellitus, renal failure, and other pathological states. 15 Asymmetrical dimethyl arginine is metabolized by dimethylarginine dimethylaminohydrolase-1 (DDAH1), and using an endothelium-specific knockout mouse model, Hu and colleagues 16 demonstrated that endothelial function is importantly regulated by endothelial DDAH1. Interestingly, the DDAH1-deficient mice were hypertensive, suggesting that the vascular endothelium is involved in blood pressure regulation. Consistent with this idea, smooth muscle cell-specific deletion of guanylyl cyclase, which is the primary target of nitric oxide, 17 is also sufficient to produce hypertension in a mouse model. 18 It is well recognized that the incidence of cardiovascular events varies by time of day and the season of the year, 19 -21 and there is growing interest in the genes that regulate circadian rhythms. 22 A recent study suggests that such genes influence vascular function. Anea and colleagues 23 observed that genetic deletion of Bmal1 and Clock in mice impaired vasodilation and eNOS signaling and induced pathological arterial remodeling responses to low blood flow. Deletion of these clock genes also increased expression of prothrombotic factors by the endothelium. These results might be relevant to circadian patterns of cardiovascular events. They also raise the possibility that disruption of the biological clock in clinical situations such as sleep deprivation or jet lag might promote cardiovascular disease. 22 Another potential mechanism of endothelial dysfunction is alteration of the signaling mechanisms involved in ...

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Role of NADPH Oxidase in Endothelial Ischemia/Reperfusion Injury in Humans

Cited by 95 publications

References 67 publications

Molecular Biology of Atherosclerosis

Molecular Biology of Atherosclerosis

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

Endothelial Function

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