Abstract
Fibrinolysis is the process by which plasmin degrades fibrin and the activity appears to depend on the balance between the tissue type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Although irradiation causes hemorrhagic tendency due to a decrease in platelets, it is likely that abnormality of fibrinolysis is involved in the hemorrhage. In this study, we investigated the effects of γ-irradiation on the fibrinolytic system of vascular endothelial cells and its mechanisms. The fibrinolytic activity in the conditioned medium of the human vascular endothelial cell line EA.hy926 increased after γ-irradiation. At that time, accumulation of both t-PA and PAI-1 proteins also increased in the conditioned medium by γ-irradiation with a higher expression of their mRNAs. On the other hand, the expression of t-PA was increased by ATP, and the γ-irradiation-induced expression of t-PA was suppressed by siRNA-mediated knockdown of either P2X4 or P2Y2. The γ-irradiation-increased expression of t-PA mRNA was suppressed by pretreatment with an Akt inhibitor, but not with a PI3K inhibitor. Although the phosphorylation of Akt protein was increased by γ-irradiation, the increase was suppressed by siRNA-mediated knockdown of either P2X4 or P2Y2. These results suggest that γ-irradiation activated fibrinolysis in the liquid phase of vascular endothelial cells by induction of t-PA synthesis, which is mediated by the P2X4/P2Y2-Akt signaling pathways activated by ATP released from damaged cells after exposure to γ-irradiation.
