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(Circulation. 2007;115:245-254.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

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

Xue Gao, MD, PhD^*; Souad Belmadani, PhD^*; Andrea Picchi, MD^*; Xiangbin Xu, PhD; Barry J. Potter, PhD; Neera Tewari-Singh, PhD; Stefano Capobianco, MD; William M. Chilian, PhD; Cuihua Zhang, MD, PhD

From the Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Tex (X.G., A.P., X.X., N.T.-S., S.C., C.Z.); and Department of Physiology, Louisiana State University Health Sciences Center, New Orleans (S.B., B.J.P., W.M.C.).

Correspondence to Cuihua Zhang, MD, PhD, Mechael E. DeBakey Institute, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4466. E-mail czhang{at}cvm.tamu.edu

Received July 9, 2006; accepted November 2, 2006.

Background— We hypothesized that the inflammatory cytokine tumor necrosis factor- (TNF) produces endothelial dysfunction in type 2 diabetes.

Methods and Results— In m Lepr^db control mice, sodium nitroprusside and acetylcholine induced dose-dependent vasodilation, and dilation to acetylcholine was blocked by the NO synthase inhibitor N^G-monomethyl-L-arginine. In type 2 diabetic (Lepr^db) mice, acetylcholine- or flow-induced dilation was blunted compared with m Lepr^db, but sodium nitroprusside produced comparable dilation. In Lepr^db mice null for TNF (db^TNF–/db^TNF–), dilation to acetylcholine or flow was greater than in diabetic Lepr^db mice and comparable to that in controls. Plasma concentration of TNF was significantly increased in Lepr^db versus m Lepr^db mice. Real-time polymerase chain reaction and Western blotting showed that mRNA and protein expression of TNF and nuclear factor-B were higher in Lepr^db mice than in controls. Administration of anti-TNF or soluble receptor of advanced glycation end products attenuated nuclear factor-B and TNF expression in the Lepr^db mice. Immunostaining results show that TNF in mouse heart is localized predominantly in vascular smooth muscle cells rather than in endothelial cells and macrophages. Superoxide generation was elevated in vessels from Lepr^db mice versus controls. Administration of the superoxide scavenger TEMPOL, NAD(P)H oxidase inhibitor (apocynin), or anti-TNF restored endothelium-dependent dilation in Lepr^db mice. NAD(P)H oxidase activity, protein expression of nitrotyrosine, and hydrogen peroxide production were increased in Lepr^db mice (compared with controls), but these variables were restored to control levels by anti-TNF.

Conclusion— Advanced glycation end products/receptor of advanced glycation end products and nuclear factor-B signaling play pivotal roles in TNF expression through an increase in circulating and/or local vascular TNF production in the Lepr^db mouse with type 2 diabetes. Increases in TNF expression induce activation of NAD(P)H oxidase and production of reactive oxidative species, leading to endothelial dysfunction in type 2 diabetes.

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