Ethanol modulation of TNF-alpha biosynthesis and signaling in endothelial cells: Synergistic augmentation of TNF-alpha mediated endothelial cell dysfunctions by chronic ethanol

Academic Article

Abstract

  • Despite reported cardio-protective effects of low alcohol intake, chronic alcoholism remains a risk factor in the pathogenesis of coronary artery disease. Dose related bimodal effects of alcohol on cardiovascular system might reflect contrasting influences of light versus heavy alcohol consumption on the vascular endothelium. Chronic ethanol induced damage to various organs has been linked to the increased release of TNF-alpha (TNF). We have previously shown that TNF, expressed at the sites of arterial injury, suppresses re-endothelialization of denuded arteries and inhibits endothelial cell (EC) proliferation in vitro. Here we report that in vitro chronic ethanol exposure enhances agonist-induced TNF mRNA and protein expression in EC. Ethanol-mediated increment in TNF expression involves increased de novo transcription without affecting mRNA stability, DNA binding assays revealed that ethanol-induced TNF up regulation was API dependent. Functionally, TNF induced EC dysfunction, including reduced proliferation, migration and cyclin A expression, were all markedly enhanced in the presence of ethanol. Additionally, expression of cyclin D1 was significantly attenuated in cells co-treated with TNF and ethanol while each treatment alone had little effect on cyclin D1 expression. Furthermore, exposure to ethanol potentiated and prolonged agonist-induced activation of JNK. Inhibition of JNK by over-expression of dominant negative JNK1 substantially reversed ethanol/TNF-mediated inhibition of cyclin A expression and EC proliferation, suggesting modulation of JNK1 signaling as the mechanism for ethanol/TNF-induced EC dysfunctions. Taken together, these data indicate that chronic ethanol consumption may negatively influence post angioplasty re-endothelialization thereby contributing to the development of restenosis. Copyright © 2005 by the Research Society on Alcoholism.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Luedemann C; Bord E; Qin G; Zhu Y; Goukassian D; Losordo DW; Kishore R
  • Start Page

  • 930
  • End Page

  • 938
  • Volume

  • 29
  • Issue

  • 6