title: The reciprocal relationship between adiponectin and LOX-1 in the regulation of endothelial dysfunction in ApoE knockout mice.
abstract: We hypothesized that the reciprocal association between adiponectin and lectin-like oxidized LDL (ox-LDL) receptor (LOX)-1 contributes to the regulation of aortic endothelial dysfunction in atherosclerosis. To test this hypothesis, endothelium-dependent (ACh) and endothelium-independent (sodium nitroprusside) vasorelaxation of isolated aortic rings from control mice, apolipoprotein E (ApoE) knockout (KO) mice, and ApoE KO mice treated with either adiponectin (15 microg x day(-1) x mouse(-1) sc for 8 days) or neutralizing antibody to LOX-1 (anti-LOX-1, 16 microg/ml, 0.1 ml/mouse ip for 7 days) were examined. Although vasorelaxation to sodium nitroprusside was not different between control and ApoE KO mice, relaxation to ACh was impaired in ApoE KO mice. Adiponectin and anti-LOX-1 restored nitric oxide-mediated endothelium-dependent vasorelaxation in ApoE KO mice. Aortic ROS formation and ox-LDL uptake were increased in ApoE KO mice. Both adiponectin and anti-LOX-1 treatment reduced ROS production and aortic ox-LDL uptake. In mouse coronary artery endothelial cells, TNF-alpha incubation increased endothelial LOX-1 expression. Adiponectin reduced TNF-alpha-induced LOX-1 expression. Consistently, in ApoE KO mice, adiponectin treatment reversed elevated LOX-1 expression in aortas. Immunofluorescence staining showed that adiponectin was mainly colocalized with endothelial cells. Although adiponectin expression was lower in ApoE KO versus control mice, anti-LOX-1 increased aortic adiponectin expression, suggesting a reciprocal regulation between adiponectin and LOX-1. Moreover, both adiponectin and anti-LOX-1 reduced NF-kappaB expression in ApoE KO mice. Thus, adiponectin and LOX-1 may converge on NF-kappaB signaling to regulate their function. In conclusion, our results indicate that the reciprocal regulation between adiponectin and LOX-1 amplifies oxidative stress and ox-LDL uptake, leading to endothelial dysfunction in atherosclerosis.
authors.affiliation: Department of Internal Medicine, Dalton CardiovascularResearch Center, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Chen
authors.forename: Hanrui
authors.initials: H
authors.lastname: Zhang
authors.forename: Steve
authors.initials: S
authors.lastname: McAfee
authors.forename: Cuihua
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D052242:Adiponectin / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D052242:Adiponectin; D001057:Apolipoproteins E; D020030:Nitric Oxide Donors; C495138:Olr1 protein, mouse; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; D014409:Tumor Necrosis Factor-alpha; D009599:Nitroprusside; D009569:Nitric Oxide; D000109:Acetylcholine