Free-radical production and function in blood vessels

Abstract

1933-1711/$ see f doi:10.1016/j.jash.20 Nicotinamide is the amide of nicotinic acid (vitamin B3/niacin). Vitamin B3 deficiency causes pellagra, as every physician knows. Nicotinamide coupled to adenine dinucleotide phosphate creates NADP, an important carrier molecule that participates in oxidation-reduction reactions (lose electrons 1⁄4 oxidation; gain electrons 1⁄4 reduction). The latter can be memorized by the mnemonic, ‘‘Leo the lion says Ger.’’ NADP can act as a high-energy electron and hydrogen ion carrier and commonly participates in coupled reactions (Figure 1). The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a membrane-bound enzyme complex active in many cells. NADPH oxidase can be found in the plasma membrane as well as in the membrane of phagosomes. The enzyme complex was initially discovered in neutrophils, where it is activated to assemble during the respiratory burst reaction. The complex generates superoxide by transferring electrons from NADPH inside the cell across the cell membrane. These electrons are coupled to molecular oxygen to produce superoxide. Why neutrophils would need NADPH oxidase seems fairly obvious. However, what good is NADPH oxidase in the membranes of vascular cells? Redox reactions are essential to life. Reactive oxygen species (ROS) act as intracellular messengers, particularly in proinflammatory signaling, leading to the activation of redox-sensitive transcription factors such as nuclear factor kappa B (NF-kB) and expression of adhesion molecules, such as selectins, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and chemokines, namely monocyte chemoattractant protein-1 (MCP-1), in the vascular endothelium. ROS may also play a crucial role in angiogenesis of endothelial cells. However, ROS are also implicated in disease, including hypertension, atherosclerosis, and stroke. Excess ROS promote lipid peroxidation and inactivate nitric oxide or foster production of highly reactive forms such as peroxinitrate. Thus, the production of ROS and the function of NADPH oxidase are major focal points of interest. The neutrophil NADPH oxidase is made up of 6 subunits (Figure 2). The subunits are the gp91 phagocytic oxidase (PHOX), p22phox, p40phox, p47phox, and p67phox. The complex generates superoxide by transferring electrons from NADPH, which resides inside the cell. The electrons are coupled to molecular oxygen (O2) to make superoxide. The H ion is given off in the process and NADP returns to the cytoplasm, waiting to be reduced again to NADPH. Thus, NADPH is a carrier of hydride ions, namely hydrogen þ 2 electrons (H ). Like ATP, NADPH is an activated carrier that participates in many important biosynthetic reactions that would otherwise be energetically unfavorable. The extra phosphate group on NADPH, compared with NADH, is far from the action and plays no role in electron transfer. However, it gives NADP a slightly different configuration, so that NADPH and NADH bind to completely different sets of enzymes. Thus, the two types of carriers are used to transfer electrons (or hydride ions) between two different sets of molecules. Unfortunately, we cannot escape semantic and abbreviation nightmares. The NADPH oxidase is generically also known as Nox, an abbreviation of an abbreviation. Until recently, the single example of ‘‘deliberate’’ generation of ROS in mammalian cells was the Nox of phagocytes (Phox; mainly neutrophils and macrophages) that catalyzes