AUTOINHIBITION OF MURINE MACROPHAGE-MEDIATED OXIDATION OF LOW-DENSITY-LIPOPROTEIN BY NITRIC-OXIDE SYNTHESIS

Murine peritoneal macrophages treated with gamma-interferon and lipopo lysaccharide (activated cells) oxidized low-density lipoprotein (LDL) less readily than unstimulated cells. Activated cells expressed the en zyme nitric oxide synthase, whose activity was measured by the accumul ation of nitrite in the culture supernatant. Treatment of activated ma crophages with the arginine analogue N(G)-monomethyl-arginine (NMMA) i nhibited nitric oxide synthesis and restored the ability of the cells to oxidize LDL. This treatment had no effect on the ability of unstimu lated cells to oxidize LDL. Similarly, LDL oxidation by activated macr ophages in arginine-free Ham's F-10 medium was identical to that of un stimulated cells, whereas restoration of arginine to the medium was as sociated with nitrite secretion and a decline in LDL oxidation by acti vated cells only. An inverse relationship between nitric oxide synthes is and LDL oxidation was also demonstrated in the presence of diphenyl ene iodonium, a flavin analogue which is a potent inhibitor of nitric oxide synthase. Thus nitric oxide synthesis appears to mediate the sup pression of LDL oxidation which is associated with the activation of m ouse macrophages by gamma-interferon and lipopolysaccharide.