Induction of mitochondrial manganese superoxide dismutase in macrophages by oxidized LDL: its relevance in atherosclerosis of humans and heritable hyperlipidemic rabbits

被引:91
作者
Kinscherf, R
Deigner, HP
Usinger, C
Pill, J
Wagner, M
Kamencic, H
Hou, DM
Chen, M
Schmiedt, W
Schrader, M
Kovacs, G
Kato, K
Metz, J
机构
[1] Univ Heidelberg, Dept Anat & Cell Biol 3, D-69120 Heidelberg, Germany
[2] Univ Heidelberg, Dept Anat & Cell Biol 2, D-69120 Heidelberg, Germany
[3] Univ Heidelberg, Inst Pharmaceut Chem, D-69120 Heidelberg, Germany
[4] Univ Heidelberg, Dept Urol, D-69120 Heidelberg, Germany
[5] Dept Cardiothorac & Vasc Surg, D-55101 Mainz, Germany
[6] Boehringer Mannheim GmbH, Dept Preclin Res, D-68298 Mannheim, Germany
[7] Aichi Human Serv Ctr, Inst Dev Res, Dept Biochem, Kasugai, Aichi 48003, Japan
关键词
antioxidants; apoptosis; glutathione; p53;
D O I
10.1096/fasebj.11.14.9409551
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The objective of the study was to analyze the intracellular antioxidative 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 atheromatous arterial tissue of humans and heritable hyperlipidemic (HHL) rabbits. Incubation of human M Phi with oxidized-LDL (ox-LDL) resulted 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 significantly increased in atherosclerotic intima compared to the media of the aorta, but significantly decreased (P < 0.01) in larger plaques compared with smaller ones, resulting in a significant inverse correlation of MnSOD activity (r = -0.67, P < 0.001) and GSH concentration (r = -0.57, P < 0.01) with plaque size. Immunohistology of the atherosclerotic 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 rabbit ones. The relation of MnSOD-ir M Phi decreased with plaque advancement, which is consistent with biochemical finding. Most MnSOD-ir M Phi in atherosclerotic plaques revealed TUNEL-positive nuclei, indicating DNA strand breaks, and p53-1R. We conclude that mitochondrial antioxidants such as MnSOD are induced in M Phi in vitro and in atherosclerotic arteries as a reply to increased mitochondrial oxidation. As normal consequences of an increased oxidative stress due to the exposure to ox-LDL nuclear DNA strand breaks occur, which are suggested to be a signal 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 apoptosis. A common response to increased oxidative stress due to modified LDL is presumed in rabbit and human atherosclerotic plaques.
引用
收藏
页码:1317 / 1328
页数:12
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