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Nitric Oxide Regulation of Free Radical– and Enzyme-Mediated Lipid and Lipoprotein Oxidation
From the Departments of Anesthesiology (A.B., B.A.F.), Biochemistry and Molecular Genetics (A.B., B.A.F.), and The Center for Free Radical Biology (A.B., B.A.F.), University of Alabama at Birmingham, and the Wales Heart Research Institute (V.B.O.), University of Wales College of Medicine, Heath Park, Cardiff, UK.
Correspondence to Bruce A. Freeman, MD, Department of Anesthesiology, 946 THT, 619 19th St South, University of Alabama at Birmingham, Birmingham, AL 35233. E-mail bruce.freeman{at}ccc.uab.edu
Abstract—The regulation of nonenzymatic and enzymatic lipid oxidation reactions by nitric oxide (·NO) is potent and pervasive and reveals novel non–cGMP-dependent reactivities for this free radical inflammatory and signal transduction mediator. ·NO and its metabolites stimulate and inhibit lipid peroxidation reactions, modulate enzymatically catalyzed lipid oxidation, complex with lipid-reactive metals, and alter proinflammatory gene expression. Through these mechanisms, ·NO can regulate nonenzymatic lipid oxidation and the production of inflammatory and vasoactive eicosanoids by prostaglandin endoperoxide synthase and lipoxygenase. The accumulation of macrophages and oxidized low density lipoprotein within the vascular wall can also be modulated by ·NO. A key determinant of the pro-oxidant versus oxidant-protective influences of ·NO is the underlying oxidative status of tissue. When ·NO 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 production are accelerated or when tissue oxidant defenses become depleted, ·NO gives rise to secondary oxidizing species that can increase membrane and lipoprotein lipid oxidation as well as foam cell formation in the vasculature, thus promoting proatherogenic effects. In summary, ·NO is a multifaceted molecule capable of reacting via multiple pathways to modulate lipid oxidation reactions, thereby impacting on tissue inflammatory reactions.
Key Words: nitric oxide • peroxynitrite • nitrogen dioxide • lipid oxidation • atherosclerosis • macrophages
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