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.
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