Open AccessTNF-α Contributes to Endothelial Dysfunction by Upregulating Arginase in Ischemia/Reperfusion Injury
Author(s) -
Xue Gao,
Xiangbin Xu,
Souâd Belmadani,
Young Joo Park,
Zhonghua Tang,
Arthur M. Feldman,
William M. Chilian,
Cuihua Zhang
Publication year - 2007
Publication title -
arteriosclerosis, thrombosis, and vascular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.007
H-Index - 270
eISSN - 1524-4636
pISSN - 1079-5642
DOI - 10.1161/atvbaha.107.142521
Subject(s) - arginase , tumor necrosis factor alpha , endothelial dysfunction , vasodilation , enos , endocrinology , cytokine , endothelium , reperfusion injury , medicine , ischemia , knockout mouse , endothelial stem cell , inflammation , nitric oxide , chemistry , nitric oxide synthase , arginine , biochemistry , in vitro , receptor , amino acid
Background— We tested whether tumor necrosis factor (TNF)-α 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-α upregulates expression of arginase in endothelial cells, which leads to O2 − production then induces endothelial dysfunction in I/R injury.