Autoinhibition of murine macrophage-mediated oxidation of low-density lipoprotein by nitric oxide synthesis

Murine peritoneal macrophages treated with γ-interferon and lipopolysaccharide (activated cells) oxidized low-density lipoprotein (LDL) less readily than unstimulated cells. Activated cells expressed the enzyme nitric oxide synthase, whose activity was measured by the accumulation of nitrite in the culture supernatant. Treatment of activated macrophages with the arginine analogue N^G-monomethyl-arginine (NMMA) inhibited nitric oxide synthesis and restored the ability of the cells to oxidize LDL. This treatment had no effect on the ability of unstimulated cells to oxidize LDL. Similarly, LDL oxidation by activated macrophages in arginine-free Ham's F-10 medium was identical to that of unstimulated cells, whereas restoration of arginine to the medium was associated with nitrite secretion and a decline in LDL oxidation by activated cells only. An inverse relationship between nitric oxide synthesis and LDL oxidation was also demonstrated in the presence of diphenylene iodonium, a flavin analogue which is a potent inhibitor of nitric oxide synthase. Thus nitric oxide synthesis appears to mediate the suppression of LDL oxidation which is associated with the activation of mouse macrophages by γ-interferon and lipopolysaccharide.