Involvement of Thromboxane Receptor in the Proatherogenic Effect of Isoprostane F2α-III

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 iPF2α-III, also known as 8-isoPGF2α 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 iPF2α-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 iPF2α-III. Endothelial cells genetically l...