on April 5, 2007
Published online before print April 5, 2007, doi: 10.1161/ATVBAHA.107.142521
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Submitted on November 23, 2006
Accepted on March 21, 2007
TNF-
Contributes to Endothelial Dysfunction by Upregulating Arginase in Ischemia/Reperfusion Injury
Xue Gao ;
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 (S.B., W.M.C.), Jefferson Medical College, Philadelphia, Pa; and the Department of Physiology (Z.T., A.M.F.), LSU Health Sciences Center, New Orleans, La.
* To whom correspondence should be addressed. 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.
Key words: coronary artery disease • ischemia • NO • microcirculation • vasodilation
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