Role of redox factor-1 in hyperhomocysteinemia-accelerated atherosclerosis.
Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. We have previously shown that homocysteine can induce monocyte chemoattractant protein-1 (MCP-1) secretion via reactive oxygen species (ROS) in human monocytes in vitro. In the present study, we investigated whether redox factor-1 (Ref-1) is involved in HHcy-accelerated atherosclerosis. We used a mild HHcy animal model, aortic roots and peritoneal macrophages were isolated for immunohistochemistry and Western blotting, from apoE-/- and C57BL/6J mice fed a high Hcy diet (1.8 g/L) for 4 or 12 weeks. Four-week HHcy apoE-/- mice showed more plaques and significantly increased immunostaining of Ref-1 and MCP-1 in foam cells, and HHcy mice showed enhanced Ref-1 expression in peritoneal macrophages. To explore the mediating mechanism, incubation with Hcy (100 microM) increased Ref-1 protein level and translocation in human monocytes in vitro. In addition, Hcy-induced NADPH oxidase activity mediated the upregulation of Ref-1. Furthermore, overexpressed Ref-1 upregulated NF-kappaB and MCP-1 promoter activity, and antisense Ref-1 reduced Hcy-induced NF-kappaB DNA-binding activity and MCP-1 secretion. These data indicate that Hcy-induced ROS upregulate the expression and translocation of Ref-1 via NADPH oxidase, and then Ref-1 increases NF-kappaB activity and MCP-1 secretion in human monocytes/macrophages, which may accelerate the development of atherosclerosis.
Dai
Jing
J
Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, Beijing 100083, People's Republic of China.
Li
Wenjing
W
Chang
Lina
L
Zhang
Zhenmin
Z
Tang
Chaoshu
C
Wang
Nanping
N
Zhu
Yi
Y
Wang
Xian
X
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000032:analysis / Q000378:metabolism*; D004032:Diet; D005260:Female; D005487:Foam Cells / Q000737:chemistry / Q000378:metabolism; D006710:Homocysteine / Q000008:administration & dosage; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D016328:NF-kappa B / Q000819:agonists; D011401:Promoter Regions, Genetic / Q000187:drug effects; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism*
D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D006710:Homocysteine; D009249:NADP; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase