Overexpression of antioxidant enzymes in ApoE-deficient mice suppresses benzo(a)pyrene-accelerated atherosclerosis.
The carcinogenic polycylic aromatic hydrocarbon, benzo(a)pyrene (BaP), has been shown to generate reactive oxygen species (ROS) and accelerate the development of atherosclerosis. To assess the causal role of BaP-generated ROS in this process, we evaluated atherosclerotic metrics in apolipoprotein E-deficient (ApoE(-/-)) mice with or without overexpression of Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and/or catalase. Without BaP, aortic atherosclerotic lesions were smaller in ApoE(-/-) mice overexpressing catalase or both Cu/Zn-SOD and catalase than in those overexpressing neither or Cu/Zn-SOD only. After treating with BaP or vehicle for 24 weeks, mean lesion sizes in the aortic tree and aortic root of ApoE(-/-) mice were increased by approximately 60% and 40%, respectively. BaP also increased the levels of oxidized lipids in the aortic tree of ApoE(-/-) mice and increased the frequency of advanced lesions. In contrast, BaP did not significantly alter lipid peroxidation levels or atherosclerotic lesions in the aortas of ApoE(-/-) mice overexpressing Cu/Zn-SOD and/or catalase. Overexpression of Cu/Zn-SOD and/or catalase also inhibited BaP-induced expression of cell adhesion molecules in aortas and endothelial cells, and reduced BaP-induced monocyte adhesion to endothelial cells. These observations, together with the functions of catalase and Cu/Zn-SOD to scavenge hydrogen peroxide and superoxide anions, implicate a causal role of ROS in the pathogenesis of BaP-induced atherosclerosis.
Yang
Hong
H
Department of Cardiovascular Biology, Meharry Medical College, Nashville, TN 37208, United States. Hyang@mmc.edu
Zhou
LiChun
L
Wang
Zefen
Z
Roberts
L Jackson
LJ
Lin
Xinghua
X
Zhao
Yanfeng
Y
Guo
ZhongMao
Z
D000818:Animals; D001018:Aortic Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001564:Benzo(a)pyrene; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology; D006801:Humans; D015227:Lipid Peroxidation; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D015854:Up-Regulation
D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D008055:Lipids; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D001564:Benzo(a)pyrene; D002374:Catalase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1