JOURNAL ARTICLE

Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species

Stephen J Wilson, Claire C Cavanagh, Allison M Lesher, Alexander J Frey, Shane E Russell, Emer M Smyth
Journal of Lipid Research 2009, 50 (6): 1047-56
19151335
Thromboxane A(2) (TxA(2)), the principle product of platelet COX-1-dependent arachidonic acid metabolism, directs multiple pro-atherogenic processes via its receptor, TP. Oxidative challenge offsets TP degradation, a key component in limiting TxA(2)'s actions. Following TP activation, we observed cellular reactive oxygen species (ROS) generation coincident with increased TP expression. We examined the link between TP-evoked ROS and TP regulation. TP expression was augmented in TPalpha-transfected cells treated with a TxA(2) analog [1S-1alpha,2beta(5Z),3alpha(1E,3R*),4alpha]]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid (IBOP). This was reduced with a cellular antioxidant, N-acetyl cysteine, or two distinct NADPH oxidase inhibitors, diphenyleneiodonium and apocynin. Homologous upregulation of the native TP was also reduced in apocynin-treated aortic smooth muscle cells (ASMCs) and was absent in ASMCs lacking an NADPH oxidase subunit (p47(-/-)). TP transcription was not increased in IBOP-treated cells, indicating a posttranscriptional mechanism. IBOP induced translocation of TPalpha to the Golgi and reduced degradation of the immature form of the receptor. These data are consistent with a ROS-dependent mechanism whereby TP activation enhanced TP stability early in posttranscriptional biogenesis. Given the significant role played by TP and ROS in perturbed cardiovascular function, the convergence of TP on ROS-generating pathways for regulation of TxA(2)-dependent events may be critical for cardiovascular disease.

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