Letter by Violi et al Regarding Article, “Molecular Imaging of Inflammation and Platelet Adhesion in Advanced Atherosclerosis Effects of Antioxidant Therapy With NADPH Oxidase Inhibition”

Abstract

Liu et al 1 have recently demonstrated that, in an animal model of atherosclerosis, apocynin, an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, halted atherosclerotic progression with a mechanism involving reduced monocyte infiltration and platelet adhesion; animals prone to atherosclerosis were also characterized by impaired artery elasticity, which was reversed by apocynin treatment. These data show that atherosclerotic progression is associated with impaired artery elasticity and suggest that inhibition of NADPH oxidase may favorably affect both. We have previously addressed this issue in a multicenter study conducted in patients with chronic granulomatous disease (CGD), which is a very rare illness characterized by hereditary deficiency of NADPH oxidase. 2The study showed that, compared with control subjects, patients with CGD had enhanced flow-mediated dilatation, a surrogate marker of atherosclerosis, suggesting that NADPH oxidase plays a role in favoring artery vasoconstriction. Enhanced flow-mediated dilatation was associated with reduced isoprostane formation, a marker of oxidative stress, and increased generation of nitric oxide, indicating that the enhanced artery elasticity was dependent on NADPH oxidase--dependent down-generation of reactive oxidant species and enhanced nitric oxide generation. In parallel with enhanced flow-mediated dilatation, patients with CGD disclosed reduced intima-media thickness, another surrogate marker of atherosclerosis, suggesting a role for NADPH oxidase in promoting functional and structural changes that are associated with the atherosclerotic process. Consistent with this hypothesis are the data from another study conducted in patients with peripheral artery disease, which is a marker of systemic atherosclerosis; in that study, patients with peripheral artery disease were characterized by upregulation of NADPH oxidase activation, which was associated with lowered flow-mediated dilatation and enhanced intima-media thickness. 3The study conducted in CGD patients is also useful in the interpretation of another interesting finding by Liu et al, 1 that is, the inhibition of platelet adhesion to the atherosclerotic plaque by apocynin treatment. Platelets from CGD had an almost complete absence of reactive oxidant species production and impaired platelet production of isoprostanes, which are proaggregating eicosanoids derived from the interaction of arachidonic acid with reactive oxidant species. 4 Thus, compared with control subjects, platelets from CGD patients showed reduced platelet recruitment, which is a marker of platelet aggregation propagation; platelet recruitment was significantly improved in platelets from CGD patients added with scalar concentration of isoprostanes.4 This result was corroborated by experiments in a flow chamber in which adhesion to collagen was reduced by platelets from CGD patients compared with control subjects; reduced adhesion was also observed with platelets from control subjects incubated with apocynin. 4 Althoug...