Regulation of Coronary Endothelial Function by Interactions between TNF-α, LOX-1 and Adiponectin in Apolipoprotein E Knockout Mice.

BACKGROUND/AIMS:Although individual contributions of TNF-α, LOX-1 and adiponectin to the regulation of endothelial function were previously studied, their interactions in the regulation of coronary endothelial function remain unclear. The aim of this study is to investigate the interactions between TNF-α, LOX-1 and adiponectin in endothelial dysfunction in atherosclerosis. METHODS:Vasodilator function was assessed in coronary arterioles isolated from wild-type, apolipoprotein (ApoE) knockout (KO) mice, ApoE KO null for TNF-α (ApoE KOTNF-/TNF-) and ApoE KO mice treated with neutralizing antibodies to either TNF-α and LOX-1, or recombinant adiponectin. Western blot analysis and immunofluorescence staining were used for mechanistic studies. RESULTS:Acetylcholine (Ach) dilation was impaired in ApoE KO mice. KO of TNF-α, anti-TNF-α anti-LOX-1 or adiponectin restored impaired ACh vasodilation without affecting endothelium-derived hyperpolarizing factor-mediated vasodilation. Immunofluorescence staining demonstrated colocalization of TNF-α with vascular smooth muscle cells, and adiponectin with endothelial cells. ApoE KO mice showed increased protein expression of LOX-1, NF-x03BA;B, NADPH oxidase subunit NOX4 and nitrotyrosine (N-Tyr) levels in coronary arterioles. Treatment with anti-TNF-α, anti-LOX-1 and adiponectin suppressed protein expression of LOX-1, NOX4, NF-x03BA;B and N-Tyr levels. CONCLUSION:Adiponectin, anti-TNF-α and anti-LOX-1 exert vasoprotective effects in atherosclerotic ApoE KO mice.