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

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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.

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Acknowledgments

This study was supported by Grants from American Heart Association Grant-in-Aid (0455435B), Atorvastatin Research Award (2004-37), American Heart Association SDG (110350047A) and NIH Grants (RO1-HL077566 and RO1-HL085119) to Dr. C Zhang.

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Authors and Affiliations

  1. Department of Internal Medicine, Medical Pharmacology and Physiology and Nutritional Sciences, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65211, USA

    Cuihua Zhang, Junxi Wu, Xiangbin Xu & Xue Gao

  2. Department of Physiology, LSU Health Sciences Center, 1901 Perdido Street, New Orleans, LA, 70112, USA

    Barry J. Potter

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  1. Cuihua Zhang
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  2. Junxi Wu
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Correspondence to Cuihua Zhang.

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Zhang, C., Wu, J., Xu, X. et al. Direct relationship between levels of TNF-α expression and endothelial dysfunction in reperfusion injury. Basic Res Cardiol 105, 453–464 (2010). https://doi.org/10.1007/s00395-010-0083-6

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  • DOI: https://doi.org/10.1007/s00395-010-0083-6

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