title: Induction of mitochondrial manganese superoxide dismutase in macrophages by oxidized LDL: its relevance in atherosclerosis of humans and heritable hyperlipidemic rabbits.
abstract: The objective of the study was to analyze the intracellular antioxidative response of macrophages (Mphi) exposed to increased levels of low density lipoprotein (LDL). We studied manganese superoxide dismutase (MnSOD) and, in part, GSH in cultured human and rabbit Mphi, and in atheromatous arterial tissue of humans and heritable hyperlipidemic (HHL) rabbits. Incubation of human Mphi 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 Mphi. 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) Mphi of human arteries and, similarly, in RAM-11-ir Mphi of rabbit ones. The relation of MnSOD-ir Mphi decreased with plaque advancement, which is consistent with biochemical findings. Most MnSOD-ir Mphi in atherosclerotic plaques revealed TUNEL-positive nuclei, indicating DNA strand breaks, and p53-IR. We conclude that mitochondrial antioxidants such as MnSOD are induced in Mphi 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.
authors.affiliation: Department of Anatomy and Cell Biology III, University of Heidelberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Kinscherf
authors.forename: H P
authors.initials: HP
authors.lastname: Deigner
authors.forename: C
authors.initials: C
authors.lastname: Usinger
authors.forename: J
authors.initials: J
authors.lastname: Pill
authors.forename: M
authors.initials: M
authors.lastname: Wagner
authors.forename: H
authors.initials: H
authors.lastname: Kamencic
authors.forename: D
authors.initials: D
authors.lastname: Hou
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: W
authors.initials: W
authors.lastname: Schmiedt
authors.forename: M
authors.initials: M
authors.lastname: Schrader
authors.forename: G
authors.initials: G
authors.lastname: Kovacs
authors.forename: K
authors.initials: K
authors.lastname: Kato
authors.forename: J
authors.initials: J
authors.lastname: Metz
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D001161:Arteriosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017931:DNA Primers; D008055:Lipids; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C099252:oxidized low density lipoprotein; D013482:Superoxide Dismutase; D005978:Glutathione