The Effect of Nitric Oxide Release Rates on the Oxidation of Human Low Density Lipoprotein

Abstract

1-Substituted diazen-1-ium-1,2-diolates, a class of nitric oxide ( ⅐ NO) donor compounds that spontaneously release ⅐ NO at different rates, were used to investigate the effect of ⅐ NO release rate upon the oxidation of low density lipoprotein (LDL). All donor compounds conferred an inhibitory effect upon the oxidation of LDL; however, the effect exhibited a biphasic dependence upon the rate of ⅐ NO release. The ⅐ NO release rate that maximally inhibited oxidation was dependent upon the rate of oxidation. When LDL was rapidly oxidized by copper(II) sulfate, a faster release rate was more effective. In contrast, when LDL was oxidized slowly by 2,2 -azobis-2-amidinopropane hydrochloride, a slower release rate was most effective. This biphasic relationship between ⅐ NO release rate and the duration of inhibition was also demonstrated when LDL oxidation was initiated with 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium, a peroxynitrite generator. We conclude that the antioxidant ability of ⅐ NO is dependent not only upon the rate of its release from ⅐ NO donors, but also upon the rate of oxidation. This conclusion is supported by a kinetic model of LDL oxidation in the presence of ⅐ NO.The chronic inhibition of nitric oxide synthase (NOS) 1 accelerates atherosclerosis in cholesterol-fed rabbits (1, 2). Supplementation of L-arginine, the substrate for NOS, has been shown to decrease fatty streak formation in rabbits and correct endothelial dysfunction in hypercholesterolemic humans (3-5). These data suggest that basal production of ⅐ NO from the vascular endothelium can suppress the changes associated with early atherosclerotic lesion formation. Moreover, augmentation of ⅐ NO production can partially counteract the effects of elevated cholesterol levels.The mechanisms by which ⅐ NO affects atherosclerotic lesion formation are unclear; however, there are many possibilities.⅐ NO has been shown to inhibit inflammatory cell adhesion to the endothelium (6) and suppress smooth muscle cell proliferation (7). In later stages of atherosclerosis, the anti-thrombolytic properties of ⅐ NO (8) may also be relevant.It has frequently been proposed that the initiation of the atherosclerotic process is oxidative in nature. Free radicalmediated oxidative damage to both the vascular endothelium and low density lipoprotein (LDL) has been proposed to be a vital component of the atherosclerotic mechanism (9, 10). We have recently shown that ⅐ NO suppresses the oxidative modification of LDL (11-13) and inhibits the toxicity of oxidized LDL to endothelial cells (14). We have proposed that the way in which ⅐ NO inhibits oxidative processes is by scavenging propagatory lipid peroxyl radicals, thus suppressing the lipid peroxidation chain reaction (11)(12)(13)(14). This mechanism will generate lipid/NO adducts that have recently been identified (15,16).Many biological effects of ⅐ NO appear to be related to the rate of ⅐ NO formation (15,17,18). Bolus delivery of high concentrations of ⅐ NO may result in limited LDL oxidation that can be augmente...

Oxidation-dependent effects of oxidized LDL: proliferation or cell death

“…The whole oxLDL induced differentiation (Parhami et al, 1993), gene expression (Han et al, 1997), cytokine production (Thomas et al, 1994;Lipton et al, 1995), inhibition of the macrophage motility (Quinn et al, 1985), cytotoxicity (Dimmeler et al, 1997), inhibition of the nitric oxide-induced vasodilatation (Liao et al, 1995;Goss et al, 1997), and mitogenicity (Auge et al, 1995;Auge et al, 1996;Chai et al, 1996). Different components of oxLDL might play roles in these various biological activities.…”

Genetic Deficiency of Inducible Nitric Oxide Synthase Reduces Atherosclerosis and Lowers Plasma Lipid Peroxides in Apolipoprotein E–Knockout Mice

“…NO may inhibit lipid peroxidation by scavenging lipid radicals and terminating the peroxidative chain reaction. 26 Conversely, NO reacts with superoxide to form peroxynitrite. Peroxynitrite can oxidize LDL, nitrosylate tyrosine residues within proteins, and generate hydroxyl radicals.…”

L-4F, an Apolipoprotein A-1 Mimetic, Restores Nitric Oxide and Superoxide Anion Balance in Low-Density Lipoprotein-Treated Endothelial Cells

“…Decreases in ·NO activity appear to develop before structural changes in the vessel wall. 28 On the basis that ·NO is a chain-breaking antioxidant that inhibits LDL oxidation, 29 platelet aggregation, 30 and smooth muscle cell proliferation, 31 it is easy to understand how a loss in ·NO activity increases atherosclerosis. If the underlying atherogenic mechanisms cannot be corrected, then logically providing ·NO may help prevent vascular disease.…”