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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1269.)
© 2007 American Heart Association, Inc.

Vascular Biology

TNF- Contributes to Endothelial Dysfunction by Upregulating Arginase in Ischemia/Reperfusion Injury

Xue Gao; Xiangbin Xu; Souad Belmadani; Yoonjung Park; Zhonghua Tang; Arthur M. Feldman; William M. Chilian; Cuihua Zhang

From the Department of Veterinary Physiology & Pharmacology (X.G., X.X., Y.P., C.Z.), Texas A&M University, College Station; the Department of Medicine (Z.T., A.M.F.), Jefferson Medical College, Philadelphia, Pa; and the Department of Physiology (S.B., W.M.C.), LSU Health Sciences Center, New Orleans, La.

Correspondence to Cuihua Zhang, MD, PhD, Michal 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

Background— We tested whether tumor necrosis factor (TNF)- increases arginase expression in endothelial cells as one of the primary mechanisms by which this inflammatory cytokine compromises endothelial function during ischemia-reperfusion (I/R) injury.

Methods and Results— Mouse hearts were subjected to 30 minutes of global ischemia followed by 90 minutes of reperfusion and their vasoactivity before and after I/R was examined in wild-type (WT), tumor necrosis factor knockout (TNF^–/–), and TNF 1.6 (TNF^++/++) mice. In WT mice, dilation to the endothelium-dependent vasodilator ACh was blunted in I/R compared with sham control. L-arginine or arginase inhibitor NOHA restored NO-mediated coronary arteriolar dilation in WT I/R mice. O₂^– production was reduced by eNOS inhibitor, L-NAME, or NOHA in WT I/R mice. In TNF^–/– mice, I/R did not alter Ach-induced vasodilation and O₂^– production compared with sham mice. The increase in arginase expression that occurs during I/R in WT mice was absent in TNF^–/– mice. Arginase expression was confined largely to the endothelium and independent of inflammatory cell invasion. Arginase activity was markedly lower in TNF^–/–, but higher in WT I/R than that in WT sham mice.

Conclusions— Our data demonstrate TNF- upregulates expression of arginase in endothelial cells, which leads to O₂^– production then induces endothelial dysfunction in I/R injury.

We tested whether TNF- increases arginase expression in endothelial cells as one of the primary mechanisms by which this inflammatory cytokine compromises endothelial function during I/R injury. Our data demonstrate TNF- upregulates expression of arginase in endothelial cells, which leads to O₂^– production, then induces endothelial dysfunction in I/R injury.

Key Words: coronary artery disease • ischemia • NO • microcirculation • vasodilation

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