Nitric oxide regulation of free radical- and enzyme-mediated lipid and lipoprotein oxidation

The regulation of nonenzymatic and enzymatic lipid oxidation reactions by n itric oxide ((NO)-N-.) is potent and pervasive and reveals novel non-cGMP-d ependent reactivities for this free radical inflammatory and signal transdu ction mediator. (NO)-N-. and its metabolites stimulate and inhibit lipid pe roxidation reactions, modulate enzymatically catalyzed lipid oxidation, com plex with lipid-reactive metals, and alter proinflammatory gene expression. Through these mechanisms, (NO)-N-. can regulate nonenzymatic lipid oxidati on and the production of inflammatory and vasoactive eicosanoids by prostag landin endoperoxide synthase and lipoxygenase. The accumulation of macropha ges and oxidized low density lipoprotein within the vascular wall can also be modulated by (NO)-N-.. A key determinant of the pro-oxidant versus oxida nt-protective influences of (NO)-N-. is the underlying oxidative status of tissue. When (NO)-N-. is in excess of surrounding oxidants, lipid oxidation and monocyte margination into the vascular wall are attenuated, producing antiatherogenic effects. However, when endogenous tissue rates of oxidant p roduction are accelerated or when tissue oxidant defenses become depleted, (NO)-N-. gives rise to secondary oxidizing species that can increase membra ne and lipoprotein lipid oxidation as well as foam cell formation in the va sculature, thus promoting proatherogenic effects, In summary, (NO)-N-. is a multifaceted molecule capable of reacting via multiple pathways to modulat e lipid oxidation reactions, thereby impacting on tissue inflammatory react ions.