title: Direct relationship between levels of TNF-alpha expression and endothelial dysfunction in reperfusion injury.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Medical Pharmacology and Physiology and Nutritional Sciences, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA. ZhangCu@missouri.edu
authors.forename: Cuihua
authors.initials: C
authors.lastname: Zhang
authors.forename: Junxi
authors.initials: J
authors.lastname: Wu
authors.forename: Xiangbin
authors.initials: X
authors.lastname: Xu
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Potter
authors.forename: Xue
authors.initials: X
authors.lastname: Gao
mesh_terms: D000109:Acetylcholine; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D001160:Arterioles / Q000201:enzymology / Q000503:physiopathology; D003331:Coronary Vessels / Q000201:enzymology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000235:genetics; D014664:Vasodilation
chemical_list: D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C544448:Arg1 protein, mouse; D001119:Arginase; D000109:Acetylcholine