NADPH oxidase-derived reactive oxygen species: involvement in vascular physiology and pathology

Abstract

Reactive oxygen species (ROS) are essential mediators of normal cell physiology. However, in the last few decades, it has become evident that ROS overproduction and/or alterations of the antioxidant system associated with inflammation and metabolic dysfunction are key pathological triggers of cardiovascular disorders. NADPH oxidases (Nox) represent a class of hetero-oligomeric enzymes whose primary function is the generation of ROS. In the vasculature, Nox-derived ROS contribute to the maintenance of vascular tone and regulate important processes such as cell growth, proliferation, differentiation, apoptosis, cytoskeletal organization, and cell migration. Under pathological conditions, excessive Nox-dependent ROS formation, which is generally associated with the up-regulation of different Nox subtypes, induces dysregulation of the redox control systems and promotes oxidative injury of the cardiovascular cells. The molecular mechanism of Nox-derived ROS generation and the means by which this class of molecule contributes to vascular damage remain debatable issues. This review focuses on the processes of ROS formation, molecular targets, and neutralization in the vasculature and provides an overview of the novel concepts regarding Nox functions, expression, and regulation in vascular health and disease. Because Nox enzymes are the most important sources of ROS in the vasculature, therapeutic perspectives to counteract Nox-dependent oxidative stress in the cardiovascular system are discussed.

Increased Benefit of Interleukin-1 Inhibition on Vascular Function, Myocardial Deformation, and Twisting in Patients With Coronary Artery Disease and Coexisting Rheumatoid Arthritis

“…At baseline, both increased IL-1β levels and oxidative stress were associated with reduced FMD and CFR. IL-1 induces NADPH oxidase expression, 18 leading to reactive oxygen species production which in turn reduces endothelial function and favors artery vasoconstriction. 19,20 Therefore, we may speculate that a larger IL-1-driven oxidative burden may have contributed to the lower FMD and CFR observed in our patients with CAD compared with those without CAD.…”

“…At baseline, both increased circulating IL-1β and oxidative stress markers were associated with reduced LV myocardial deformation and twistinguntwisting, as well as with reduced EF in our patients with CAD. IL-1 activity may cause reversible myocardial dysfunction through (1) a direct detrimental effect on cardiac mitochondria as well as on mitochondrial respiratory chain, 21 and (2) reduction of endothelial nitric oxide synthase [22][23][24] and production of inducible nitric oxide synthase, 7,23,24 intracellular reactive oxygen species, 18 peroxynitrate, 16 and cytokines with a negative inotropic action such as interleukin-6. 25,26 In patients with CAD, the prepercutaneous intervention levels of IL-1β contributed to prediction of LV end-systolic volume, and postpercutaneous intervention levels of IL-1β determined LV volumes.…”

Enzymatic Targets in Atherosclerosis

“…NOX activation also involves GTP-binding protein, Rac1/2 or Rap 1A. The structure and function of NADPH oxidases are presented in detail by Maneaȋ [114]. The cells involved in atherosclerosis express NADPH oxidases.…”

Vascular Biology of Reactive Oxygen Species and NADPH Oxidases: Role in Atherogenesis

“…H 2 O 2 may be completely reduced to H 2 O by means of various peroxidases such as catalase and glutathione peroxidase or partially reduced to HO•, one of the most powerful oxidizing agent identified in biological systems. The generation of HO• is mediated by various free transition metal ions (e.g., Fe 2+ , Cu 2+ ) via the Haber-Weiss reaction (Manea, 2010). Apart from the aforementioned chemical processing of O 2 , superoxide can react with other molecular species including nitrogen species such as nitric oxide (NO) or polyunsaturated fatty acids.…”

“…Interestingly, a positive feed-back loop of Nox activation by NF-kB has been proposed in several studies. Thus, a new integrative concept has emergedthe "vicious cycle", to describe the interconnection between metabolic dysfunction, inflammation, and oxidative stress that converges to vascular disorders (Manea, 2010). In murine monocytes, the expression of the Nox2 is induced by NF-kB.…”