Direct relationship between levels of TNFα expres

Authors: Cuihua Zhang Junxi Wu Xiangbin Xu Barry J Potter Xue Gao

Publish Date: 2010/01/21

Volume: 105, Issue: 4, Pages: 453-464

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Abstract

We previously found that myocardial ischemia/reperfusion I/R initiates expression of tumor necrosis factorα 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 cardiacspecific expression of TNF acetylcholineinduced or flowinduced endothelialdependent vasodilation following I/R was between TNF++/++ and TNF−/− following I/R Neutralizing antibodies to TNF administered immediately before the onset of reperfusionpreserved endothelialdependent dilation following I/R in WT TNF−/++ and TNF++/++ mice In WT TNF−/++ and TNF++/++ mice I/Rinduced endothelial dysfunction was progressively lessened by administration of freeradical scavenger TEMPOL immediately before initiating reperfusion During I/R production of superoxide O2 ·− 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

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