Abstract | BACKGROUND: METHODS AND RESULTS: TP antagonism with S18886, but not combined inhibition of COX-1 and COX-2 with indomethacin or selective inhibition of COX-2 with Merck Frosst ( MF) tricyclic, retards significantly atherogenesis in DKOs. Although indomethacin depressed urinary excretion of major metabolites of both TxA2, 2,3-dinor TxB2 (Tx-M), and PGI2, 2,3-dinor 6-keto PGF(1alpha) (PGI-M), only PGI-M was depressed by the COX-2 inhibitor. None of the treatments modified significantly the increase in lipid peroxidation during atherogenesis, reflected by urinary 8,12-iso-iPF(2alpha)-VI. Combination with the COX-2 inhibitor failed to augment the impact of TP antagonism alone on lesion area. Rather, analysis of plaque morphology reflected changes consistent with destabilization of the lesion coincident with augmented formation of TxA2. Despite a marked effect on disease progression, TP antagonism failed to induce regression of established atherosclerotic disease in this model. CONCLUSIONS: TP antagonism is more effective than combined inhibition of COX-1 and COX-2 in retarding atherogenesis in Apobec-1/LDLR DKO mice, which perhaps reflects activation of the receptor by multiple ligands during disease initiation and early progression. Despite early intervention, selective inhibition of COX-2, alone or in combination with a TP antagonist, failed to modify disease progression but may undermine plaque stability when combined with the antagonist. TP antagonism failed to induce regression of established atherosclerotic disease. TP ligands, including COX-1 (but not COX-2)-derived TxA2, promote initiation and early progression of atherogenesis in Apobec-1/LDLR DKOs but appear unimportant in the maintenance of established disease.
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Authors | Karine M Egan, Miao Wang, Susanne Fries, Margaret B Lucitt, Alicia M Zukas, Ellen Puré, John A Lawson, Garret A FitzGerald |
Journal | Circulation
(Circulation)
Vol. 111
Issue 3
Pg. 334-42
(Jan 25 2005)
ISSN: 1524-4539 [Electronic] United States |
PMID | 15655126
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Cyclooxygenase 2 Inhibitors
- Cyclooxygenase Inhibitors
- Dietary Fats
- Furans
- Membrane Proteins
- Naphthalenes
- Propionates
- Receptors, Thromboxane
- 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone
- Thromboxane A2
- terutroban
- Cyclooxygenase 1
- Cyclooxygenase 2
- Prostaglandin-Endoperoxide Synthases
- Ptgs1 protein, mouse
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Topics |
- Animals
- Aorta
(pathology)
- Arteriosclerosis
(metabolism, pathology, prevention & control)
- Cyclooxygenase 1
- Cyclooxygenase 2
- Cyclooxygenase 2 Inhibitors
- Cyclooxygenase Inhibitors
(pharmacology)
- Dietary Fats
(administration & dosage)
- Drug Interactions
- Furans
(pharmacology)
- Membrane Proteins
- Mice
- Naphthalenes
(pharmacology)
- Propionates
(pharmacology)
- Prostaglandin-Endoperoxide Synthases
(metabolism)
- Receptors, Thromboxane
(antagonists & inhibitors)
- Thromboxane A2
(metabolism)
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