Direct relationship between levels of TNF-α expression and endothelial dysfunction in reperfusion injury

• DOI: 10.1007/s00395-010-0083-6
• Publication Date: 2010-01-20T20:09:38Z
• Authors: Cuihua Zhang; Junxi Wu; Xiangbin Xu; Barry J. Potter; Xue Gao
• Keywords: Mice, Knockout; Arginase; Nitric Oxide Synthase Type III; Tumor Necrosis Factor-alpha; R; 610; Myocardial Reperfusion Injury; In Vitro Techniques; Nitric Oxide; Coronary Vessels; Acetylcholine; Vasodilation; Arterioles; Mice; 03 medical and health sciences; 0302 clinical medicine; Superoxides; 616; Medicine; Animals; Endothelium, Vascular

We previously found that myocardial ischemia/reperfusion (I/R) initiates expression of tumor necrosis factor-alpha (TNF) leading to coronary endothelial dysfunction. However, it is not clear whether there is a direct relationship between levels of TNF expression and endothelial dysfunction in reperfusion injury. We studied levels of TNF expression by using different transgenic animals expressing varying amounts of TNF in I/R. We crossed TNF overexpression (TNF(++/++)) with TNF knockout (TNF(-/-)) mice; thus we have a heterozygote population of mice with the expression of TNF "in between" the TNF(-/-) and TNF(++/++) mice. Mouse hearts were subjected to 30 min of global ischemia followed by 90 min of reperfusion and their vasoactivity before and after I/R was examined in wild type (WT), TNF(-/-), TNF(++/++) and TNF heterozygote (TNF(-/++), cross between TNF(-/-) and TNF(++/++)) mice. In heterozygote TNF(-/++) mice with intermediate cardiac-specific expression of TNF, acetylcholine-induced or flow-induced endothelial-dependent vasodilation following I/R was between TNF(++/++) and TNF(-/-) following I/R. Neutralizing antibodies to TNF administered immediately before the onset of reperfusion-preserved endothelial-dependent dilation following I/R in WT, TNF(-/++) and TNF(++/++) mice. In WT, TNF(-/++) and TNF(++/++) mice, I/R-induced endothelial dysfunction was progressively lessened by administration of free-radical scavenger TEMPOL immediately before initiating reperfusion. During I/R, production of superoxide (O(2) (.-)) was greatest in TNF(++/++) mice as compared to WT, TNF(-/++) and TNF(-/-) mice. Following I/R, arginase mRNA expression was elevated in the WT, substantially elevated in the TNF(-/++) and TNF(++/++) mice and not affected in the TNF(-/-) mice. These results suggest that the level of TNF expression determines arginase expression in endothelial cells during myocardial I/R, which is one of the mechanisms by which TNF compromises coronary endothelial function in reperfusion injury.