Nitric Oxide, NAD(P)H Oxidase, and Atherosclerosis

Abstract

The endothelial cell layer plays a major role in the development and progression of atherosclerosis. Endothelial NO synthase (eNOS) produces nitric oxide (NO) from L-arginine. NO can rapidly react with reactive oxygen species to form peroxynitrite. This reduces NO availability, impairs vasodilatation, and mediates proinflammatory and prothrombotic processes such as leukocyte adhesion and platelet aggregation. In the vessel wall, specific NAD(P)H oxidase complexes are major sources of reactive oxygen species. These NAD(P)H oxidases can transfer electrons across membranes to oxygen and generate superoxide anions. The short-lived superoxide anion rapidly dismutates to hydrogen peroxide, which can further increase the production of reactive oxygen species. This can lead to uncoupling of eNOS switching enzymatic activity from NO to superoxide production. This review describes the structure and regulation of different NAD(P)H oxidase complexes. We will also focus on NO/superoxide anion balance as modulated by hemodynamic forces, vasoconstrictors, and oxidized low-density lipoprotein. We will then summarize the recent advances defining the role of nitric oxide and NAD(P)H oxidase-derived reactive oxygen species in the development and progression of atherosclerosis. In conclusion, novel mechanisms affecting the vascular NO/superoxide anion balance will allow the development of therapeutic strategies in the treatment of cardiovascular diseases.

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

“…It has now become evident that the spatial and temporal regulation of reactive nitrogen and oxygen species generation can dictate the functional impact of these signaling molecules on the homeostatic maintenance of vascular function, where dysregulation can lead to complications including, but not limited to, endothelial dysfunction, inflammation, and atherosclerosis (reviewed by Giles, 2006;Pacher et al, 2007;Muller and Morawietz, 2009). The biologic half-life of NO is extremely short (,5 seconds), because of the rapid diffusion to surrounding cells, chemical reactions with other cellular oxidants, and scavenging by heme-containing proteins, most notably hemoglobin (Nathan, 1992;Archer, 1993;Hakim et al, 1996).…”

Hemodynamic Regulation of Reactive Oxygen Species: Implications for Vascular Diseases

“…However, there are marked differences among the NOX homologues (Table 1). NOX 1, 2, 4, and 5 are variably expressed in different vascular cell types (93). NOX1 is predominantly expressed in VSMCs, and, to a lesser extent, in ECs.…”

Adiponectin as a Link Between Type 2 Diabetes and Vascular NADPH Oxidase Activity in the Human Arterial Wall: The Regulatory Role of Perivascular Adipose Tissue

“…NADPH oxidase, a potent source of superoxide anions (O 2 _ 2 ) in the vascular wall (1), is directly implicated in atherogenesis (2)(3)(4). The presence of type 2 diabetes has been related to increased activity of NADPH oxidase in the vascular wall, which is considered to be a key feature in the vascular complications of type 2 diabetes (5).…”