An excessive generation of superoxide may be a central component of a number of cardiovascular diseases including hypertension, atherosclerosis and hyper-lipidemia.56 One of the mechanisms by which this free radical contributes to hypertension is the inactivation of NO generated from endothelial cells. Endogenous endothelium-derived NO regulates blood pressure by vasodilation. The coupling of superoxide ions with NO decreases its availability; thus, overproduction of superoxide diminishes blood vessel tone and promotes hyperten-sion.34 In spontaneously hypertensive rats, treatment with the SOD mimetic M40403 removed superoxide anions and prompted the return to near-normal blood pressure. It was unclear whether this restoration of function was due to prolonged half-life of NO or inhibited formation of peroxynitrite.
Superoxide and its product, peroxynitrite, also participate in the development of atherosclerotic lesions (hardening of the arteries) by stimulating lipid peroxidation. In addition, a lack of nitric oxide due to overproduction of superoxide may promote proliferation of smooth muscle cells and release of pro-inflammatory molecules in the vascular wall. All of these events advance the progression of atherosclerosis and restenosis (a recurrent narrowing of heart valve or artery after corrective surgery).56 A major generator of superoxide ions in vascular tissues is ^-nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase; an up-regulation of this enzyme has been implicated in the etiology of cardiovascular diseases. Jiang etal.56 tested the impact of the SODm M40403 on superoxide generated from this oxidase in aorta from apolipopro-tein (E)-deficient (apoE0) mice, animals that develop atherosclerosis, hypertension and hyperlipidemia. The removal of superoxide generated from NAD(P)H oxidase reversed the endothelial dysfunction in these apoE0 mice.
These results suggest a clinical application for this mimetic in diseases related to superoxide and endothelial dysfunction, such as hypertension and diabetes, inflammation and ischemia/reperfusion. One caution, however, may be that the mimetic may increase the level of H2O2 which also potentiates vascular pathology.31
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