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.

α-Lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway

“…The PI3K/Akt pathway is a conserved family of signal transduction enzymes that are involved in regulating cellular proliferation and survival. A growing body of evidence suggests that the PI3K/Akt pathway plays an important role as a negative feedback regulator of excessive innate immune and Toll-like receptor-mediated proinflammatory responses (15)(16)(17)(18)(19)(20)(21)(22). Hence, inhibition of PI3K/Akt signaling enhanced LPS-induced activation of NF-B and AP-1 and gene expression of TNF␣ and tissue factor in cultured cells (15).…”

“…This is important because there are substantial differences among different cell types regarding the antiinflammatory role of the PI3K/Akt pathway. It has been reported that this pathway either acts as a positive (40)(41)(42) or negative regulator (15,18,19) of NF-B activation and cytokine production, depending on the nature of the stimulus and the cell type.…”

“…The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway has been shown to play an important role in negatively regulating LPS-induced acute inf lammatory responses in vitro and in vivo (15)(16)(17)(18)(19)(20)(21). Inhibition of PI3K/Akt signaling enhances LPS-induced activation of NF-B, AP-1, and Egr-1 transcription factors and gene expression of TNF␣ and tissue factor in cultured human monocytic cells (15).…”

“…Similar effects were observed in vivo, where inhibition of PI3K/Akt enhanced LPS-induced coagulation and inflammation in endotoxemic mice (16). Conversely, activation of the PI3K/Akt pathway by glucan phosphate (17) or angiopoietin-1 (18) inhibited TNF␣-induced tissue factor expression in endothelial cells (18) and was correlated with increased survival in a cecal ligation and puncture (CLP) septic mouse model (17). Furthermore, transgenic overexpression of Akt has been shown to protect against septic death in the CLP mouse model (19) as well as mice infected with the Gram-negative bacterium Francisella (20).…”

The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells

“…Induction of nitric-oxide synthase in C6 glial cells and rat primary astrocytes was also regulated negatively by activation of PI3K (17), and a constitutively active PI3K inhibited induction of nitricoxide synthase gene expression in human astrocytes (25). Angiopoeitin-1, a potent activator of PI3K, negatively regulated vascular endothelial growth factor-and TNF-␣-induced TF expression in endothelial cells (26). Finally, in endothelial cells the PI3K-Akt pathway limited vascular endothelial growth factor activation of the p38 MAPK pathway and TF gene expression (27).…”