title: TNF-alpha contributes to endothelial dysfunction by upregulating arginase in ischemia/reperfusion injury.
abstract: BACKGROUND
  We tested whether tumor necrosis factor (TNF)-alpha increases arginase expression in endothelial cells as one of the primary mechanisms by which this inflammatory cytokine compromises endothelial function during ischemia-reperfusion (I/R) injury.
  
  
  RESULTS
  Mouse hearts were subjected to 30 minutes of global ischemia followed by 90 minutes of reperfusion and their vasoactivity before and after I/R was examined in wild-type (WT), tumor necrosis factor knockout (TNF-/-), and TNF 1.6 (TNF++/++) mice. In WT mice, dilation to the endothelium-dependent vasodilator ACh was blunted in I/R compared with sham control. L-arginine or arginase inhibitor NOHA restored NO-mediated coronary arteriolar dilation in WT I/R mice. O2(-) production was reduced by eNOS inhibitor, L-NAME, or NOHA in WT I/R mice. In TNF-/- mice, I/R did not alter Ach-induced vasodilation and O2(-) production compared with sham mice. The increase in arginase expression that occurs during I/R in WT mice was absent in TNF-/- mice. Arginase expression was confined largely to the endothelium and independent of inflammatory cell invasion. Arginase activity was markedly lower in TNF-/-, but higher in WT I/R than that in WT sham mice.
  
  
  CONCLUSIONS
  Our data demonstrate TNF-alpha upregulates expression of arginase in endothelial cells, which leads to O2(-) production then induces endothelial dysfunction in I/R injury.
authors.affiliation: Department of Veterinary Physiology & Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Gao
authors.forename: Xiangbin
authors.initials: X
authors.lastname: Xu
authors.forename: Souad
authors.initials: S
authors.lastname: Belmadani
authors.forename: Yoonjung
authors.initials: Y
authors.lastname: Park
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Tang
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
authors.forename: William M
authors.initials: WM
authors.lastname: Chilian
authors.forename: Cuihua
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C404735:N(omega)-hydroxynorarginine; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D001120:Arginine; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D001119:Arginase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester