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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1695.)
© 2000 American Heart Association, Inc.

Editorials

TP or Not TP: Primary Mediators in a Close Runoff?

Domenico Praticó; Yan Cheng; Garret A. FitzGerald

From the Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia.

Correspondence to Dr G.A. FitzGerald, Center for Experimental Therapeutics, 153 Johnson Pavillion, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. E-mail garret@@spirit.gcrc.upenn.edu

Key Words: Editorials • thromboxane • atherosclerosis • isoprostane • oxidant stress

Aspirin has emerged as a remarkably safe, inexpensive, and effective drug for the secondary prevention of the complications of atherosclerotic disease. It acts by inhibiting the enzyme prostaglandin (PG) G/H synthase, actually a bifunctional protein that sequentially catalyzes the conversion of arachidonic acid to the highly reactive endoperoxide intermediates PGG₂ and PGH₂ via its cyclooxygenase (COX) and peroxidase functions. This enzyme, colloquially termed COX, has been crystallized¹ and the mechanism of action of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) elucidated.^{2 3 4} The catalytic site is buried deep within the core of the enzyme and is accessed by the substrate via a hydrophobic tunnel. Aspirin irreversibly acetylates a serine residue at position 529 in the human enzyme,⁵ close to but not at the catalytic site, though still blocking access to it by the arachidonic acid substrate. NSAIDs, by contrast, act reversibly as competitive inhibitors at the catalytic site. Indeed, transient occupancy of that site after dosing with an NSAID may mask the serine from the effects of a subsequent dose of aspirin.⁶

The beneficial effects of aspirin in cardiovascular disease have been attributed to its inhibitory effects on COX in platelets. In these cells, thromboxane (Tx) synthase further catalyzes the conversion of PGH₂ to TxA₂,⁷ which exerts proaggregatory, vasoconstrictor, and proliferative effects via a membrane-bound, G protein–coupled receptor, the TP.⁸ Two isoforms ( and ß) of the TP have been cloned,^{8 9} both of which are transcribed in human platelets, although only TP appears to be translated.¹⁰ Transcripts of both isoforms are . . . [Full Text of this Article]

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