OXIDATIVE STRESS, ANTIOXIDANTS AND EDRF ACTION

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This proposal is based on the hypothesis that antioxidants limit the clinical manifestations of coronary artery disease in patients by preserving EDRF action. Abnormalities of EDRF action develop early in atherosclerosis and are related, in part, to excess local vascular oxidative stress and accumulation of oxidized low-density lipoprotein (LDL). Recent studies and preliminary data presented in this application strongly suggest that an imbalance between oxidative stress and antioxidant defenses in the vascular wall contribute to the development of impaired EDRF action. The overall objectives are to examine the protection afforded by the resident vascular cell content of antioxidants with respect to cell-mediated LDL oxidation, the cellular production of reactive oxygen species such as superoxide anion and hydrogen peroxide, and the preservation of EDRF action in response to oxidative insult. The primary experimental model for this proposal will be cultured bovine aortic endothelial and smooth muscle cells. The relevance of these effects for LDL oxidation in vivo will be assessed using a new model of LDL oxidation by intact arterial segments. Our research will determine the effects of these antioxidants on cellular production of reactive oxygen species such as superoxide anion and hydrogen peroxide and begin investigation into the mechanism(s) responsible for these effects. In particular, the relationship of these effects on superoxide and hydrogen peroxide production with antioxidant-mediated effects on LDL oxidation and EDRF action will be studied. We will investigate the role of vascular antioxidant content in preserving EDRF action in response to a variety of oxidative insults including reactive oxygen species and oxidized LDL. The work contained in this proposal will provide new insights into the mechanism(s) by which antioxidants provide benefit for patients with atherosclerosis. In particular, this work will help establish the role of vascular antioxidant content in the preservation of important homeostatic functions such as local vascular EDRF action.