PPARα调节PAI-1活性的分子机理

It is well known that high plasminogen activator inhibitor-1(PAI-1)level and activity, as the risk factors for atherosclerosis, are obviously associated with hypertriglyceridemia. The mechanism of the association remains imprecise. Feeding on fatty acids up-regulate level of PAI-1 and fatty acids can acivate peroxisome proliferator-activated receptors(PPARs). Therefore we hypothesized that PPARs might play a role in regulating gene transcription involved in linking hypertriglyceridemia and high PAI-1 levels and PAI-1 might be a PPARs target gene. We investigated the mechanism via diverse techniques of cell biology and molecular biology in human umbilical vein endothelial cells(HUVECs) and human hepatoblastome (HepG2)cells in vitro. Both in cultured HUVECs and HepG2 cells, polyunsaturated fatty acids augnent the expression of PAI-1 at mRNA and protein levels in a dose-dependent manner. However, the mRNA expressions of PPARs with their activators（e.g.fatty acids and prostaglandin J2） in both HUVECs and HepG2 cells were not changed compared with controls. We observed for the first time that PAI-1 transcriptional activity was signifivantly enhanced by PPARαplasmid co-transfection to ECV304 and polyunsaturated fatty acids enhanced the effects,but no change in PAI-1 transcriptional activity was observed when the expression of PPARγwas increased.Our results showed for the first time internationlly that hypertriglyceridemia affects the level of PAI-1 and PPARαinvolves in the regulating process at least in part，which is one of the molecular mechanism that hypertriglyceridemia affects the activity of fibrinolysis system clinically.

本课题以FAs作为PPARa的激活物，以研究PPARa和相关的转录因子的作用为基点，探讨FAs激活PPARa对PAI-1活性的影响及其分子机理；同时研究PPARa或转录因子激活在高甘油三酯血⒃黾覲AI-1活性中的作用。