Antiapoptotic effect of coagulation factor VIIa

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Factor VIIa (FVIIa) binding to tissue factor (TF) triggers intracellular signaling pathways implicated in angiogenesis, tumor metastasis, and restenosis.
• The precise mechanisms by which TF-mediated signaling influences cellular fate, particularly apoptosis, remain incompletely understood.

Purpose of the Study:

• To investigate the effect of FVIIa on apoptosis in cells expressing tissue factor.
• To elucidate the signaling pathways involved in FVIIa-mediated protection against apoptosis.

Main Methods:

• Serum deprivation was used to induce apoptosis in BHK cells stably expressing TF (BHK(+TF)).
• Apoptosis was assessed by morphological changes, DNA fragmentation (TUNEL assay), and caspase 3 activation.
• The role of specific signaling pathways was examined using inhibitors for PI3-kinase (LY294002) and MEK (U0126).

Main Results:

• FVIIa significantly reduced the incidence of apoptotic morphology and DNA degradation in serum-deprived BHK(+TF) cells.
• FVIIa attenuated the activation of caspase 3, indicating an antiapoptotic effect.
• This protective effect was dependent on FVIIa's proteolytic activity and TF expression, but not on factor Xa or thrombin.
• FVIIa-induced cell survival correlated with Akt activation and was significantly inhibited by LY294002, while U0126 only modestly impaired survival.

Conclusions:

• FVIIa binding to TF confers protection against apoptosis induced by growth factor deprivation.
• The primary signaling pathway mediating this effect is PI3-kinase/Akt, with a secondary contribution from the p44/42 MAPK pathway.