TNF-alpha contributes to endothelial dysfunction by upregulating arginase in ischemia/reperfusion injury

Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1269-75. doi: 10.1161/ATVBAHA.107.142521. Epub 2007 Apr 5.

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.

Methods and 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Animals
  • Arginase / antagonists & inhibitors
  • Arginase / biosynthesis*
  • Arginine / analogs & derivatives
  • Arginine / metabolism*
  • Arginine / pharmacology
  • Coronary Vessels / drug effects
  • Coronary Vessels / enzymology*
  • Coronary Vessels / physiopathology
  • Disease Models, Animal
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / enzymology*
  • Endothelium, Vascular / physiopathology
  • Enzyme Induction
  • Enzyme Inhibitors / pharmacology
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Myocardial Reperfusion Injury / enzymology
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / physiopathology
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Neutrophils / enzymology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / metabolism
  • Nitric Oxide Synthase Type III
  • Peroxidase / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Superoxides / metabolism
  • Tumor Necrosis Factor-alpha / deficiency
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Vasodilation* / drug effects
  • Vasodilator Agents / pharmacology

Substances

  • Enzyme Inhibitors
  • N(omega)-hydroxynorarginine
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Vasodilator Agents
  • Superoxides
  • Nitric Oxide
  • Arginine
  • Peroxidase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • Arginase
  • Acetylcholine
  • NG-Nitroarginine Methyl Ester