Erschienen in:
01.07.2010 | Original Contribution
Direct relationship between levels of TNF-α expression and endothelial dysfunction in reperfusion injury
verfasst von:
Cuihua Zhang, Junxi Wu, Xiangbin Xu, Barry J. Potter, Xue Gao
Erschienen in:
Basic Research in Cardiology
|
Ausgabe 4/2010
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Abstract
We previously found that myocardial ischemia/reperfusion (I/R) initiates expression of tumor necrosis factor-α (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 (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.