ACTIVATION OF THROMBOXANE RECEPTOR BY ENDOGENOUS LIGANDS

血栓烷（Tx）A2通过G蛋白偶联受体TP介导其作用。它是血小板中环氧合酶（考克斯）-1和人动脉粥样硬化中单核细胞和血管平滑肌细胞中诱导的考克斯-2的主要产物。除了其同源配体，异前列烷（iPs），花生四烯酸的自由基催化的前列腺素异构体产物，也可以作为TP的附带配体。目前的建议是为了扩大我们的研究TP激活，包括血小板与血管壁的相互作用。在具体目标1中，我们将研究TP激活在调节动脉粥样硬化形成和血管损伤反应中的作用。将在动脉粥样硬化的Apobec-1/LDL受体双敲除（DKO）小鼠模型中检查TP拮抗作用和TP缺失的作用。在存在和不存在TP的情况下，使用维生素E滴定iP抑制的效果将用于评价iP对TP激活的贡献。同样，将检查拮抗作用和TP缺失对导管诱导损伤反应的影响。将使用前列环素受体（IP）缺陷的小鼠来确定围手术期阿司匹林对PGI 2形成的抑制是否可能限制TP拮抗作用在预防血管成形术后再狭窄中的功效。在具体目标2中，我们将确定是否由于IP缺乏或暴露于香烟烟雾诱导的考克斯激活和氧化应激而加重了由TP定向血管过度表达的妊娠小鼠胎盘缺血引起的宫内生长迟缓。同样，To拮抗剂和滴定剂量的维生素E将用于检查同源和偶然配体对TP活化的贡献。最后，在具体目标3中，我们将进行一项随机前瞻性、双盲对照试验，以确定血小板考克斯-1、考克斯-2或两者的抑制是否延缓冠状动脉粥样硬化患者斑块体积的进展，如EBCT和B模式超声检查所评估的。

Thromboxane (Tx) A2 mediates its effects via a G protein coupled receptor, the TP. It is a major product of cyclooxygenase (COX)-1 in platelets and of COX-2, which is induced in monocytes and vascular smooth muscle cells in human atherosclerosis. Additional to its cognate ligand, isoprostanes (iPs), free radical catalyzed prostaglandin isomeric products of arachidonic acid, may also act as incidental ligands at the TP. The present proposals are designed to extend our studies of TP activation to encompass platelet interactions with the vessel wall. In Specific Aim 1, we shall examine the role of TP activation in modulating atherogenesis and the response to vascular injury. The effect of TP antagonism and TP deletion will be examined in the Apobec-1/LDL receptor double knock out (DKO) mouse model of atherosclerosis. The effect of titrated iP suppression with vitamin E in the presence and absence of the TP will be utilized to evaluate the contributions of iPs to TP activation. Similarly, the impact of antagonism and TP deletion on the response to catheter induced injury will be examined. Mice deficient in the prostacyclin receptor (IP) will be used to determine whether depression of PGI2 formation by periprocedural aspirin might limit the efficacy of TP antagonism in the prevention of restonosis after angioplasty. In Specific Aim 2, we shall determine whether intrauterine growth retardation, which results from placental ischemia in pregnant mice with directed vascular over-expression of the TP, is exacerbated by coincidental IP deficiency or by COX activation and oxidant stress induced by exposure to cigarette smoke. Again, To antagonists and titrated doses of vitamin E will be used to examine the contribution from cognate and incidental ligands to TP activation. Finally, in Specific Aim 3, we shall perform a randomized prospective, double blind controlled trial to determine if inhibition of platelet COX-1, COX-2 or both retard the progression of plaque volume, as assessed by EBCT and B mode ultrasonography in patients with coronary atherosclerosis.