Regulatory role of vHL/HIF-1alpha in hypoxia-induced VEGF production in hepatic stellate cells

Biochem Biophys Res Commun. 2004 Apr 30;317(2):358-62. doi: 10.1016/j.bbrc.2004.03.050.

Abstract

Activated hepatic stellate cells (HSCs) produce cyclooxygenase-2 (COX-2) protein to induce vascular endothelial growth factor (VEGF) production that participates in angiogenesis in injured liver. To reveal the unknown regulatory mechanism, we used hypoxic atmosphere mimicking injured-tissue microenvironment to induce VEGF expression in a rat hepatic stellate cell line (T6-HSCs). The present study showed that hypoxia up-regulated the protein levels of COX-2 and hypoxia-inducible factor-1-alpha (HIF-1alpha), but rapidly effected degradation of von Hippel-Lindau (vHL) protein. As a result, expression of VEGF in HSCs was markedly elevated; and pretreatment with COX-2 inhibitors (nimesulide or indomethacin) could significantly ameliorate the angiogenic event. Collectively, hypoxic HSCs increased accumulation of HIF-1alpha protein and induced VEGF expression in a time-dependent manner. Inhibition of COX-2 activities would prevent vHL protein from degradation and suppress HIF-1alpha up-regulation. Thus, vHL/HIF-1alpha has a regulatory role in COX-2-mediated VEGF production in hypoxic stellate cells in injured liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / physiology*
  • Cell Line
  • Cyclooxygenase 2
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Homeostasis / physiology*
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indomethacin / pharmacology
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism*
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Rats
  • Sulfonamides / pharmacology
  • Transcription Factors / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Carrier Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Isoenzymes
  • Sulfonamides
  • Transcription Factors
  • VBP1 protein, human
  • Vascular Endothelial Growth Factor A
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • nimesulide
  • Indomethacin