Involvement of thromboxane receptor in the proatherogenic effect of isoprostane F2alpha-III: evidence from apolipoprotein E- and LDL receptor-deficient mice.
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 iPF2alpha-III, also known as 8-isoPGF2alpha 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.


RESULTS
In this study we show that iPF2alpha-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 iPF2alpha-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 iPF2alpha-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 iPF2alpha-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.
Tang
Myan
M
Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
Cyrus
Tillmann
T
Yao
Yuemang
Y
Vocun
Luigina
L
Praticò
Domenico
D
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D028421:Isoprostanes / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D028421:Isoprostanes; D011973:Receptors, LDL; D017482:Receptors, Thromboxane; C438786:isoprostane F2alpha III; C045749:SQ 29548