Regulatory role of vHL/HIF-1alpha in hypoxia-induced VEGF production in hepatic stellate cells.
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.
Wang
Yang Q
YQ
Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
Luk
John M
JM
Ikeda
Kazuo
K
Man
Kwan
K
Chu
Andrew C
AC
Kaneda
Kenji
K
Fan
Sheung Tat
ST
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018832:Molecular Chaperones; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D018832:Molecular Chaperones; D013449:Sulfonamides; D014157:Transcription Factors; C108825:VBP1 protein, human; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C012655:nimesulide; D007213:Indomethacin