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J. Biol. Chem., Vol. 279, Issue 9, 8316-8324, February 27, 2004

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The Mechanism of Oxidative Stress Stabilization of the Thromboxane Receptor in COS-7 Cells^*

François Valentin, Mark C. Field¶, and John R. Tippins||

From the Department of Biological Sciences and the Wellcome Trust Laboratories for Molecular Parasitology, Imperial College, Exhibition Road, London SW7 2AZ, United Kingdom

The 8-iso-prostaglandin F₂, a prostanoid produced in vivo by cyclooxygenase-independent free-radical-catalyzed lipid peroxidation, acts as a partial agonist on the thromboxane receptor (TXA₂R) and is a potent vasoconstrictor in the oxidatively stressed isolated perfused rat heart. We hypothesized that the response in the isolated heart may be due to augmentation of TXA₂R density, which may be initiated by the presence of oxidative radicals. Previous studies have shown that TXA₂R density is increased during atherosclerosis on both the medial and intimal smooth muscle layers in human coronary arteries. Here we describe the effect of oxidative stress on TXA₂R. The thromboxane A₂ receptor isoform (TXA₂R) was transiently expressed in COS-7 cells. Immunofluorescence suggested that the presence of H₂O₂ increased translocation of TXA₂R from the endoplasmic reticulum (ER) to the Golgi complex. H₂O₂ treatment also increased binding of a TXA₂R antagonist ([³H]SQ29548) to membranes. Degradation kinetics of TXA₂R following cycloheximide treatment, a protein synthesis inhibitor, suggested not only that TXA₂R is a short-lived protein predominantly localized to the ER but also that TXA₂R degradation is modulated in the presence of H₂O₂. Our results indicate that oxidative stress induces maturation and stabilization of the TXA₂R protein probably by intracellular translocation. Importantly, these observations also suggest that TXA₂R levels are modulated by ER-associated degradation and controlled by the efficiency of transport to post-ER compartments. Stabilization of the TXA₂R by translocation from a degradative compartment, i.e. the ER, can account for the augmentation of receptor density observed in vivo.

Received for publication, June 25, 2003 , and in revised form, October 16, 2003.

^* This work was supported by British Heart Foundation Grant PG/2000119 (to J. R. T. and M. C. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence may be addressed. Tel./Fax: 44-020-7594-5277; E-mail: m.field{at}imperial.ac.uk.

^|| To whom correspondence may be addressed. Tel.: 44-020-7594-5216; Fax: 44-020-7594-5300; E-mail: j.tippins{at}imperial.ac.uk.

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