SUPPRESSING NADPH OXIDASE-DEPENDENT OXIDATIVE STRESS IN THE VASCULATURE WITH NITRIC OXIDE DONORS

1. Reactive oxygen species produced in the vasculature, including superoxide anion, contribute to the pathogenesis of cardiovascular disease states, such as atherosclerosis. A critical source of superoxide is vascular NADPH oxidase and upregulation of this enzyme brings about the oxidative stress underlying atherosclerosis. Excessive superoxide in arteries directly inactivates endothelium-derived nitric oxide (NO), compromising its vasoprotective effects. 2. Given that a reduction in NO bioavailability is key in the pathophysiology of atherosclerosis, replacement of NO by exogenously administered NO donors may restore the deficit in NO during disease. Although the organic nitrate family of NO donors is often the first choice for the acute management of symptoms of atherosclerosis and angina pectoris, most of the compounds in this class are unsuitable for long-term therapy because they cause oxidative stress by activation and upregulation of vascular NADPH oxidase and induce tolerance to subsequent nitrate treatment and endogenous NO. These problems of nitrates have not only limited their therapeutic exploitation, but have also stifled interest in newer-generation NO donors. 3. Recent evidence indicates that, in stark contrast with the organic nitrates, the newer-age diazeniumdiolate NONOate class of NO donors suppress vascular NADPH oxidase-dependent superoxide production and are less likely to induce tolerance, making them more suitable for suppression of oxidative stress in atherosclerosis. 4. Here, it is hypothesized that NONOates provide a novel means of suppressing NADPH oxidase-dependent oxidative stress to restore vascular NO levels to prevent, and even reverse, atherosclerosis.