Tumor Necrosis Factor-α Induces Endothelial Dysfunction in Lepr db Mice

• DOI: 10.1161/circulationaha.106.650671
• Publication Date: 2007-01-03T02:57:14Z
• Authors: Xue Gao; Souad Belmadani; Andrea Picchi; Xiangbin Xu; Barry J. Potter; Neera Tewari-Singh; Stefano Capobianco; William M. Chilian; Cuihua Zhang
• Keywords: Sodium nitroprusside; Apocynin; Endothelial Dysfunction

Background— We hypothesized that the inflammatory cytokine tumor necrosis factor-α (TNF) produces endothelial dysfunction in type 2 diabetes. Methods and Results— In m Lepr db control mice, sodium nitroprusside acetylcholine induced dose-dependent vasodilation, dilation to was blocked by NO synthase inhibitor N G -monomethyl- l -arginine. diabetic (Lepr ) acetylcholine- or flow-induced blunted compared with , but produced comparable dilation. mice null for TNF (db − /db ), flow greater than controls. Plasma concentration of significantly increased versus mice. Real-time polymerase chain reaction Western blotting showed mRNA protein expression nuclear factor-κB were higher Administration anti-TNF soluble receptor advanced glycation end products attenuated Immunostaining results show mouse heart is localized predominantly vascular smooth muscle cells rather macrophages. Superoxide generation elevated vessels from superoxide scavenger TEMPOL, NAD(P)H oxidase (apocynin), restored endothelium-dependent activity, nitrotyrosine, hydrogen peroxide production (compared controls), these variables levels anti-TNF. Conclusion— Advanced products/receptor signaling play pivotal roles through an increase circulating and/or local Increases induce activation reactive oxidative species, leading