Studies onfanction of prostacyclin and thromboxane in vascular disorders

前列环素(PGI_2)和血栓烷(TX)是花生四烯酸衍生的脂质介质，对血管系统的稳态起着重要作用。然而，它们的具体作用机制仍不清楚。为了研究前列环素(PGI_2)、血栓素(TX)和前列腺素(PG)E_2在心血管疾病中的作用，对转基因小鼠和这些生物合成酶的高表达细胞进行了研究。主要研究结果如下：1.PGI_2合成酶基因突变所致的PGI_2缺陷型(PGID)小鼠发生了包括肾脏和主动脉动脉硬化在内的血管病变。与野生型小鼠相比，PGID小鼠血浆和组织中的血栓素和前列腺素E_2水平升高。基因芯片分析发现，除细胞外基质基因表达上调外，促炎症细胞因子和/或相关基因的mRNA水平也升高。2.内皮细胞中PGI2合酶的过度表达诱导了一定的抗炎细胞因子的产生。在该细胞因子基因的5‘上游区域发现了PPAAR反应元件的5个重复序列，PGI2-PPAR-Delta信号通路参与了该细胞因子的诱导。3.分析了膜相关PGE合成酶的基因结构和转录调控，发现转录因子Egr-1是该酶表达所必需的。

Prostacyclin (PGI_2) and thromboxane (TX) are lipid mediators derived from arachidonic acid and play important role for homeostasis of vascular system. However, their detail mechanism of function is still unclear. In order to study the role of PGI_2, TX and prostaglandin (PG) E_2 in the cardiovascular diseases, the genetically modified mice and the overexpressing cells of these biosynthetic enzymes. The obtained results are as follows.1.PGI_2-deficient (PGID) mice generated by genetic disruption of PGI_2 synthase gene developed vascular disorders including arteriosclerosis in the kidneys and aorta. In PGID mice, thromboxane and PGE_2 levels in plasma and tissues rose compared with those of wild-type mice. The increase in mRNA revels of pro-inflammatory cytokines and/or those related genes was observed in addition to the elevated expression of genes for extracellular matrix by gene chip analysis.2.The overexpression of PGI_2 synthase in endothelial cells induced a certain anti-inflammatory cytokine. Five repeats of the consensus sequence of PPAAR responsive element were found in the 5' upstream region of this cytokine gene and the PGI_2-PPAR-delta signaling pathway was involved in the induction of the cytokine.3.Gene structure and transcriptional regulation of membrane associated PGE synthase were analyzed and a transcriptional factor, Egr-1 was essential for the expression of the enzyme.