title: Angiopoietin-1 negatively regulates expression and activity of tissue factor in endothelial cells.
abstract: Normally, tissue factor (TF) is not expressed on the surface of endothelial cells, but its expression can be induced by vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)-a. However, the signaling pathway(s) affecting this induction is unknown. Using human umbilical vein endothelial cells, we found that inhibitors of guanine-cytosine-rich DNA binding protein and nuclear factor (NF)-kB suppressed VEGF- and TNF-a-induced expression and activity of TF. However, unexpectedly, phosphatidylinositol (PI) 3'-kinase inhibitor enhanced the VEGF- and TNF-a-induced expression and activity of TF. Angiopoietin-1 (Ang1), a strong activator of intracellular PI 3'-kinase/Akt, inhibited the induction of TF by VEGF and TNF-a, whereas Ang1 itself did not produce any significant effect on TF. Selective activation (or inactivation) of PI 3'-kinase/Akt by using adenoviral transfer reduced (or enhanced) TNF-a-induced expression of TF mRNA and protein, regardless of Ang1 treatment. From these results, we conclude that Ang1 inhibits the up-regulation of TF expression, possibly through activation of PI 3'-kinase/Akt in endothelial cells. Ang1 may be useful as an inhibitor of VEGF- and TNF-a-induced coagulation, inflammation, and cancer progression.
authors.affiliation: National Creative Research Initiatives Center for Endothelial Cells and Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Injune
authors.initials: I
authors.lastname: Kim
authors.forename: Jong-Lark
authors.initials: JL
authors.lastname: Oh
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Ryu
authors.forename: June-No
authors.initials: JN
authors.lastname: So
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
mesh_terms: D042683:Angiopoietin-1; D002478:Cells, Cultured; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007700:Kinetics; D008222:Lymphokines / Q000037:antagonists & inhibitors; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008954:Models, Biological; D012333:RNA, Messenger / Q000096:biosynthesis; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013925:Thromboplastin