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.