Studies onfanction of prostacyclin and thromboxane in vascular disorders

前列环素（PGI_2）和血栓素（TX）是由花生四烯酸衍生的脂质介质，在维持血管系统的稳态中起重要作用。但其具体作用机制尚不清楚。为了研究前列环素（PGI_2）、前列腺素（TX）和前列腺素E_2（PG E_2）在心血管疾病中的作用，本研究采用转基因小鼠和高表达这些生物合成酶的细胞，对转基因小鼠的心血管疾病模型进行了研究。结果表明：1. PGI_2合成酶基因缺失的PGID小鼠，在肾脏和主动脉出现动脉硬化等血管病变。PGID小鼠血浆和组织中血栓素和前列腺素E_2水平较野生型小鼠升高。基因芯片检测结果显示，内皮细胞中除细胞外基质相关基因表达增加外，促炎细胞因子和/或其相关基因的mRNA水平也增加。2.内皮细胞中PGI_2合成酶的过表达可诱导一定的抗炎细胞因子。在该细胞因子基因的5'上游区域发现了5个重复的PPAAR反应元件的共有序列，并通过PGI_2-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Egr-1是该酶表达所必需的转录因子。

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.