title: NADPH Oxidase-2 and Atherothrombosis: Insight From Chronic Granulomatous Disease.
abstract: The phagocytic cell enzyme NADPH oxidase-2 (Nox2) is critical for killing micro-organisms via production of reactive oxygen species and thus is a key element of the innate immune system. Nox2 is also detectable in endothelial cells and platelets where it has vasoconstrictive and aggregating properties, respectively. Patients with X-linked chronic granulomatous disease with hereditary Nox2 deficiency not only have impaired bacterial killing but, in association with loss of Nox2 function, also have enhanced carotid artery dilation, impaired platelet-related thrombosis, and reduced carotid atherosclerotic burden. Experimental studies corroborated these reports in chronic granulomatous disease by demonstrating (1) Nox2 is upregulated in atherosclerotic plaque, and this upregulation significantly correlates with oxidative stress and (2) pharmacological inhibition of Nox2 is associated with a delayed atherosclerotic progression in animal models. Furthermore, the role of Nox2 in platelet-associated thrombosis was substantiated by experiments showing impaired platelet activation in animals treated with a Nox2 inhibitor or impaired platelet aggregation along with reduced platelet-related thrombosis in the mouse knockout model of Nox2. Interestingly, in chronic granulomatous disease patients and in the mouse knockout model of Nox2, no defects of primary hemostasis were detected. This review analyses experimental and clinical data suggesting Nox2 is a potential target for counteracting the atherothrombotic process.
authors.affiliation: From the Division of I Clinica Medica, Policlinico Umberto I, Sapienza University, Rome, Italy (F.V., L.L., P.P.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C.); and Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (J.I.G.). francesco.violi@uniroma1.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Violi
authors.affiliation: From the Division of I Clinica Medica, Policlinico Umberto I, Sapienza University, Rome, Italy (F.V., L.L., P.P.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C.); and Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (J.I.G.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Carnevale
authors.affiliation: From the Division of I Clinica Medica, Policlinico Umberto I, Sapienza University, Rome, Italy (F.V., L.L., P.P.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C.); and Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (J.I.G.).
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Loffredo
authors.affiliation: From the Division of I Clinica Medica, Policlinico Umberto I, Sapienza University, Rome, Italy (F.V., L.L., P.P.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C.); and Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (J.I.G.).
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pignatelli
authors.affiliation: From the Division of I Clinica Medica, Policlinico Umberto I, Sapienza University, Rome, Italy (F.V., L.L., P.P.); Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy (R.C.); and Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (J.I.G.).
authors.forename: John I
authors.initials: JI
authors.lastname: Gallin
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006105:Granulomatous Disease, Chronic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D058226:Plaque, Atherosclerotic; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013927:Thrombosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control
chemical_list: D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D010975:Platelet Aggregation Inhibitors; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: atherosclerosis; eicosanoids; foam cells; monocytes; oxidative stress