NADPH Oxidases: Functions and Pathologies in the Vasculature

Abstract

Abstract-Reactive oxygen species are ubiquitous signaling molecules in biological systems. Four members of the NADPH oxidase (Nox) enzyme family are important sources of reactive oxygen species in the vasculature: Nox1, Nox2, Nox4, and Nox5. Signaling cascades triggered by stresses, hormones, vasoactive agents, and cytokines control the expression and activity of these enzymes and of their regulatory subunits, among which p22phox, p47phox, Noxa1, and p67phox are present in blood vessels. Vascular Nox enzymes are also regulated by Rac, ClC-3, Poldip2, and protein disulfide isomerase. Multiple Nox subtypes, simultaneously present in different subcellular compartments, produce specific amounts of superoxide, some of which is rapidly converted to hydrogen peroxide. The identity and location of these reactive oxygen species, and of the enzymes that degrade them, determine their downstream signaling pathways. Nox enzymes participate in a broad array of cellular functions, including differentiation, fibrosis, growth, proliferation, apoptosis, cytoskeletal regulation, migration, and contraction. They are involved in vascular pathologies such as hypertension, restenosis, inflammation, atherosclerosis, and diabetes. As our understanding of the regulation of these oxidases progresses, so will our ability to alter their functions and associated pathologies. Key Words: atherosclerosis Ⅲ blood vessels Ⅲ hypertension Ⅲ NADPH oxidase Ⅲ reactive oxygen species O ur knowledge of the signaling role of reactive oxygen species (ROS) in vascular physiology and pathophysiology has expanded tremendously in the past 15 years. NADPH oxidases (Nox) have emerged as major sources of ROS in the vasculature, multiple Nox subtypes have been cloned and analyzed structurally and functionally, and the relationship of Nox enzymes to signaling pathways, cellular function, and vascular disease has begun to be investigated.The Nox family consists of 7 catalytic homologues, 4 of which (Nox1, Nox2, Nox4, and Nox5) are found in the vasculature. These enzymes transfer electrons from NADPH to molecular oxygen, thus producing superoxide (O 2 ⅐Ϫ ). Because O 2 ⅐Ϫ does not readily cross membranes and is short-lived, its effect is mostly local. Depending on Nox subcellular location, O 2 ⅐Ϫ is released either inside organelles or extracellularly, with corresponding internal signaling or paracrine effects. Superoxide dismutase rapidly converts O 2 ⅐Ϫ to longer-lasting and membrane-diffusible H 2 O 2 , thus modifying the signal and expanding its range of action. Whereas some effects of Nox enzymes, such as inactivation of nitric oxide (NO ⅐ ) in blood pressure regulation, are mediated directly by O 2 ⅐Ϫ , many are instead attributable to protein modification by H 2 O 2 , including growth-related signal transduction in vascular smooth muscle cells (VSMC).In this brief review, we discuss our current understanding of vascular NADPH oxidases, especially their roles in physiology and disease. We first describe each oxidase separately, before presenting an overview of...

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

“…ROS production is increased in VSMCs from resistance arteries of hypertensive patients, and this is associated with up-regulation of vascular Nox (75,112,142,207,213,233). The importance of Nox in human cardiovascular disease is supported by studies showing that polymorphisms in Nox subunits are associated with increased atherosclerosis and hypertension.…”

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“…Characterization of Noxes as they pertain to vascular biology and hypertension has recently been reviewed. 76,77 In vessels, in addition to vascular cells possessing functional Noxes, resident macrophages, neutrophils and platelets express NAD(P)H oxidase, particularly in pathological states. Accordingly these cells can also contribute to vascular oxidative stress in disease.…”

ROS-mediated downregulation of MYPT1 in smooth muscle cells: a potential mechanism for the aberrant contractility in atherosclerosis

“…18 In the vasculature, NADPH oxidases are critical factors for the aberrant ROS production in various disorders. 19 Cumulative evidence indicated that oxidative stress from increased production or insufficient removal of ROS aids the progression of atherosclerosis. 18,19 Our previous study demonstrated that long-term oral estrogen treatment reduces ROS levels and atherosclerosis progression in apolipoprotein E-knockout (apoE-KO) mice, which suggests atheroprotective effects via anti-oxidative actions.…”

“…19 Cumulative evidence indicated that oxidative stress from increased production or insufficient removal of ROS aids the progression of atherosclerosis. 18,19 Our previous study demonstrated that long-term oral estrogen treatment reduces ROS levels and atherosclerosis progression in apolipoprotein E-knockout (apoE-KO) mice, which suggests atheroprotective effects via anti-oxidative actions. 20 The bioavailability of endothelium-derived NO is negatively modulated by the presence of superoxide, as these two molecules react with high affinity to produce peroxynitrite (ONOO À ).…”