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

Abstract

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. O 2 − 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 O 2 − 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 O 2 − production then induces endothelial dysfunction in I/R injury.