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

Cuihua Zhang, Junxi Wu, Xiangbin Xu, Barry J. Potter, Xue Gao

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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, acetyl-choline-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.

Original languageEnglish
Pages (from-to)453-464
Number of pages12
JournalBasic Research in Cardiology
Issue number4
Publication statusPublished - 1 Jul 2010


  • coronary artery disease
  • ischemia
  • microcirculation
  • NO
  • vasodilation


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