PAI-1 GENE EXPRESSION IS INDUCED BY FLUID SHEAR STRESS IN RAT HEPATOCYTE

Abstract

A186 Aims: Liver sinusoidal cells are always exposed to mechanical stress arising from sinusoidal blood flow. In the remnant liver after hepatectomy or non occluded lobe in the portal branch embolization or graft liver in liver transplantation, it is possible that increasing shear stress effects hepatocyte directory and modulate liver regeneration or liver damage. Some investigators have shown its possibility but there are few reports about shear stress and gene expression of hepatocyte. Plasminogen activator inhibitor-1 (PAI-1) is known to be induced transiently in the early phase of liver regeneration but its mechanism and function are still unclear. We loaded shear stress to the cultured hepatocyte and studied PAI-1 gene expression. Methods: 1. Rat hepatocyte were cultured on glass plate and set in the parallel chamber. Fluid shear stress was loaded to the hepatocyte. PAI-1 mRNA expression was analyzed by the real time PCR and compared with static control. Luciferase assay and nuclear run-on asasy were performed to study their transcriptional activity. 2. Wistar rat weighed 450g was used to confirm hemodynamic change. Portal vein branch responsible for about 70% of liver was ligated and portal vein pressure was measured by direct cannulation and sinusoidal blood velocity, flow rate and vascular area were analyzed in non ligated lobe by use of laser doppler flow meter. Then PAI-1 mRNA expression in the non ligated liver tissue was also studied. 3. Plasma PAI-1 level in the recipients of living donor liver transplantation were measured before and after reperfusion of the graft liver. Results: After loading shear stress (10dynes/cm2) for six hours PAI-1 mRNA expression was increased transiently to 6.7 fold of static control. Compared with normal medium and that added 5% dextran, PAI-1 mRNA expression was induced more in the latter at any flow rate. Transcriptional activity was also increased. Portal pressure was increased after portal branch ligation and sinusoidal blood velocity and flow rate were increased 40% significantly. PAI-1 mRNA level in non ligated liver tissue was risen up to 40 times at three hours after ligation. Plasma PAI-1 level after blood reperfusion was higher than before perfusion. Conclusions: PAI-1 mRNA expression was induced by fluid shear stress in rat hepatocyte. It is suggested that PAI-1 gene expression in the remnant liver after hepatectomy or graft liver in liver transplantation is induced by increased shear stress arisen from sinusoidal blood flow.