INDUCTION OF MITOCHONDRIAL MANGANESE SUPEROXIDE-DISMUTASE IN MACROPHAGES BY OXIDIZED LDL - ITS RELEVANCE IN ATHEROSCLEROSIS OF HUMANS AND HERITABLE HYPERLIPIDEMIC RABBITS

The objective of the study was to analyze the intracellular antioxidat ive response of macrophages (M Phi) exposed to increased levels of low density lipoprotein (LDL). We studied manganese superoxide dismutase (MnSOD) and, in part, GSH in cultured human and rabbit M Phi, and in a theromatous arterial tissue of humans and heritable hyperlipidemic (HH L) rabbits. Incubation of human M Phi with oxidized-LDL (ox-LDL) resul ted in an induction of MnSOD mRNA production as shown by RT-PCR. MnSOD immunoreactivity (IR) was found to be located in the mitochondria of M Phi. In HHL rabbits, MnSOD activity and GSH concentration were signi ficantly increased in atherosclerotic intima compared to the media of the aorta, but significantly decreased (P < 0.01) in larger plaques co mpared with smaller ones, resulting in a significant inverse correlati on of MnSOD activity (r = -0.67, P < 0.001) and GSH concentration (r = -0.57, P < 0.01) with plaque size. Immunohistology of the atheroscler otic intima revealed MnSOD-IR in Mac-1 (CD 11b/CD 18)-immunoreactive ( ir) M Phi of human arteries and, similarly, in RAM-11-ir M Phi, of rab bit ones. The relation of MnSOD-ir M Phi decreased with plaque advance ment, which is consistent with biochemical finding. Most MnSOD-ir M Ph i in atherosclerotic plaques revealed TUNEL-positive nuclei, indicatin g DNA strand breaks, and p53-1R. We conclude that mitochondrial antiox idants such as MnSOD are induced in M Phi in vitro and in atherosclero tic arteries as a reply to increased mitochondrial oxidation. As norma l consequences of an increased oxidative stress due to the exposure to ox-LDL nuclear DNA strand breaks occur, which are suggested to be a s ignal to increase p53 protein levels. Reactive oxygen species-mediated mitochondrial-dependent pathways are suggested as major contributing pathomechanisms to nuclear damage, which eventually may result in apop tosis. A common response to increased oxidative stress due to modified LDL is presumed in rabbit and human atherosclerotic plaques.