This Article Full Text Full Text (PDF) All Versions of this Article: 115/2/245    most recent CIRCULATIONAHA.106.650671v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gao, X. Articles by Zhang, C. Search for Related Content PubMed PubMed Citation Articles by Gao, X. Articles by Zhang, C. Related Collections Type 2 diabetes Coronary circulation Oxidant stress Endothelium/vascular type/nitric oxide

(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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				M. Tesauro, F. Schinzari, V. Rovella, D. Melina, N. Mores, A. Barini, M. Mettimano, D. Lauro, M. Iantorno, M. J. Quon, et al. Tumor Necrosis Factor-{alpha} Antagonism Improves Vasodilation During Hyperinsulinemia in Metabolic Syndrome Diabetes Care, July 1, 2008; 31(7): 1439 - 1441. [Abstract] [Full Text] [PDF]

				S. Belmadani, D. I. Palen, R. A. Gonzalez-Villalobos, H. A. Boulares, and K. Matrougui Elevated Epidermal Growth Factor Receptor Phosphorylation Induces Resistance Artery Dysfunction in Diabetic db/db Mice Diabetes, June 1, 2008; 57(6): 1629 - 1637. [Abstract] [Full Text] [PDF]

				E. Jebelovszki, C. Kiraly, N. Erdei, A. Feher, E. T. Pasztor, I. Rutkai, T. Forster, I. Edes, A. Koller, and Z. Bagi High-fat diet-induced obesity leads to increased NO sensitivity of rat coronary arterioles: role of soluble guanylate cyclase activation Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2558 - H2564. [Abstract] [Full Text] [PDF]

				N. G. Abraham and A. Kappas Pharmacological and Clinical Aspects of Heme Oxygenase Pharmacol. Rev., March 1, 2008; 60(1): 79 - 127. [Abstract] [Full Text] [PDF]