Apocynin, NADPH Oxidase, and Vascular Cells

Abstract

Apocynin (4-hydroxy-3-methoxyacetophenone), isolated from the traditional medicinal plant Picrorhiza kurroa , is a naturally occurring methoxy-substituted catechol, experimentally used as an inhibitor of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase.1 Activated neutrophil NADPH oxidase, a multisubunit complex composed of membrane-associated gp91phox (Nox2) and p22phox and cytosolic subunits, p47phox, p67phox, and p40phox, produces superoxide anion, a precursor of microbicidal reactive oxygen species (ROS), thereby playing a crucial role in host defense. Apocynin inhibits the release of superoxide anion by NADPH oxidase by blocking migration of p47phox to the membrane, critically involved in initiating assembly of the functional NADPH oxidase complex.1 The underlying chemistry of apocynin’s actions has been elucidated in phagocytic cells.2 Apocynin needs to be activated (oxidized) for it to inhibit the oxidase. In the presence of H2O2 and myeloperoxidase (MPO), abundant in neutrophils, apocynin is oxidized and has as products dimer and trimer derivatives resulting in diapocynin formation, the metabolically active compound of apocynin. The reactivity of apocynin radical with thiol compounds is possibly the mechanism involved in the inhibitory effect of apocynin on the NADPH oxidase complex.2,3 In the early 1990s, with the discovery that cardiovascular cells possess functionally active NADPH oxidase critically involved in ROS generation and oxidative stress in the vascular wall, many investigators extended neutrophil findings and used apocynin as a pharmacological agent to specifically inhibit the vascular cell oxidase. Convincing data from numerous in vitro studies demonstrated that, in endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts, apocynin blocks NADPH oxidase activity and superoxide anion generation.4,5 In vivo studies, in which mice and …