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。它是环氧合酶(COX)-1在血小板中的主要产物，也是COX-2在单核细胞和血管平滑肌细胞中诱导的主要产物，在人类动脉粥样硬化中。除了其同源配体异前列腺素(IPS)外，自由基催化的花生四烯酸前列腺素异构体产物也可能是TP的附带配体。目前的建议旨在扩大我们对TP激活的研究，以涵盖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对血管损伤的反应中的作用。在APOBEC-1/低密度脂蛋白受体双敲除(DKO)小鼠动脉粥样硬化模型上观察TP拮抗和TP缺失的作用。在TP存在和不存在的情况下，维生素E滴定IP抑制的效果将被用来评估iPS对TP激活的贡献。同样，拮抗和TP缺失对导管诱导损伤的反应的影响也将被检测。前列环素受体(IP)缺陷的小鼠将被用来确定围手术期阿司匹林抑制PGI2的形成是否会限制TP拮抗剂预防血管成形术后再狭窄的效果。在特定的目标2中，我们将确定是巧合的IP缺乏还是由于暴露在香烟烟雾中引起的COX激活和氧化应激加剧了妊娠小鼠胎盘缺血和TP血管定向过表达导致的宫内生长迟缓。同样，对于拮抗剂和滴定剂量的维生素E将被用来检查同源配体和附带配体对TP激活的贡献。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，以确定抑制血小板COX-1、COX-2或两者是否延缓了斑块体积的进展，如EBCT和B超在冠状动脉粥样硬化患者中所评估的那样。

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.