Involvement of thromboxane receptor in the proatherogenic effect of isoprostane F-2 alpha-III Evidence from apolipoprotein E- and LDL receptor-deficient mice

Article

关键词: 8-EPI-PROSTAGLANDIN F-2 ALPHA;    IN-VIVO FORMATION;    LIPID-PEROXIDATION;    8-ISO-PROSTAGLANDIN F2-ALPHA;    PLATELET ACTIVATION;    SERUM PARAOXONASE;    ATHEROGENESIS;    ATHEROSCLEROSIS;    F-2-ISOPROSTANES;    INFLAMMATION;   

DOI  :  10.1161/CIRCULATIONAHA105.562223

来源: SCIE

【 摘 要 】

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 iPF(2 alpha)-III, also known as 8-isoPGF(2 alpha) 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 iPF(2 alpha)-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 A(2) levels, changes in blood pressure, or lipid profile. Pharmacological antagonism of TP suppresses the vascular proatherogenic effects of iPF(2 alpha)-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 iPF(2 alpha)-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 iPF(2 alpha)-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.

【 授权许可】

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