NAD(P)H Oxidase–Dependent Self-Propagation of Hydrogen Peroxide and Vascular Disease

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Abstract
Excessive production of reactive oxygen species in the vasculature contributes to cardiovascular pathogenesis. Among biologically relevant and abundant reactive oxygen species, superoxide (O 2 ·− ) and hydrogen peroxide (H 2 O 2 ) appear most important in redox signaling. Whereas O 2 ·− predominantly induces endothelial dysfunction by rapidly inactivating nitric oxide (NO · ), H 2 O 2 influences different aspects of endothelial cell function via complex mechanisms. This review discusses recent advances establishing a critical role of H 2 O 2 in the development of vascular disease, in particular, atherosclerosis, and mechanisms whereby vascular NAD(P)H oxidase–derived H 2 O 2 amplifies its own production. Recent studies have shown that H 2 O 2 stimulates reactive oxygen species production via enhanced intracellular iron uptake, mitochondrial damage, and sources of vascular NAD(P)H oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase (eNOS). This self-propagating phenomenon likely prolongs H 2 O 2 -dependent pathological signaling in vascular cells, thus contributing to vascular disease development. The latest progress on Nox functions in vascular cells is also discussed [Nox for N AD(P)H ox idases, representing a family of novel NAD(P)H oxidases].