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(Circulation. 2005;112:2867-2874.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Involvement of Thromboxane Receptor in the Proatherogenic Effect of Isoprostane F₂-III

Evidence From Apolipoprotein E– and LDL Receptor–Deficient Mice

Myan Tang, PhD; Tillmann Cyrus, MD; Yuemang Yao, BSc; Luigina Vocun, BSc; Domenico Praticò, MD

From the Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia (M.T., Y.Y., L.V., D.P.), and Division of Cardiology, Washington University, St Louis, Mo (T.C.).

Correspondence to Domenico Praticò, MD, University of Pennsylvania, Department of Pharmacology, 3620 Hamilton Walk, John Morgan Bldg, Rm 124, Philadelphia, PA 19104. E-mail domenico{at}spirit.gcrc.upenn.edu

Received May 13, 2005; revision received August 8, 2005; accepted August 10, 2005.

Background— Atherosclerosis is a chronic inflammatory disease of the arterial wall, where it associates with oxidative stress and formation of oxidized lipids. The lipid oxidation product isoprostane iPF₂-III, also known as 8-isoPGF₂ and 15-F2t-IsoP, is elevated in patients with cardiovascular disease and present in atherosclerotic lesions. Several proatherogenic biological effects have been attributed to this isoprostane, suggesting that it could be an active factor in the pathogenesis of the disease.

Methods and Results— In this study we show that iPF₂-III directly promotes atherogenesis in 2 different mouse models (ie, apolipoprotein E [apoE]– and LDL receptor–deficient mice) by activating the thromboxane receptor (TP). This effect is mediated by potent proinflammatory vascular reactions but is independent of thromboxane A₂ levels, changes in blood pressure, or lipid profile. Pharmacological antagonism of TP suppresses the vascular proatherogenic effects of iPF₂-III. Endothelial cells genetically lacking TP show reduced inflammatory responses when stimulated with this product of lipid oxidation but not other oxidized lipids.

Conclusions— Our results demonstrate that in atherosclerosis iPF₂-III is not only a biomarker of oxidative stress but also an active mediator of its vascular phenotype. We conclude that in a clinical setting in which both thromboxane A₂ and iPF₂-III are elevated, suppression of the first alone would not provide the most benefit for patients because the coincidental presence of the isoprostane will still have a proatherogenic effect.

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