Cyclooxygenases, thromboxane, and atherosclerosis -: Plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism

被引:162
|
作者
Egan, KM
Wang, M
Lucitt, MB
Zukas, AM
Puré, E
Lawson, JA
FitzGerald, GA
机构
[1] Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA
[2] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA
[3] Ludwig Inst Canc Res, Philadelphia, PA USA
关键词
thromboxane; atherosclerosis; lesion; prostaglandins; inflammation;
D O I
10.1161/01.CIR.0000153386.95356.78
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background - Antagonism or deletion of the receptor (the TP) for the cyclooxygenase (COX) product thromboxane (Tx) A(2), retards atherogenesis in apolipoprotein E knockout (ApoE KO) mice. Although inhibition or deletion of COX-1 retards atherogenesis in ApoE and LDL receptor (LDLR) KOs, the role of COX-2 in atherogenesis remains controversial. Other products of COX-2, such as prostaglandin (PG) I-2 and PGE(2), may both promote inflammation and restrain the effects of TxA(2). Thus, combination with a TP antagonist might reveal an antiinflammatory effect of a COX-2 inhibitor in this disease. We addressed this issue and the role of TxA2 in the promotion and regression of diffuse, established atherosclerosis in Apobec-1/LDLR double KOs (DKOs). 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 TxA(2), 2,3-dinor TxB(2) ( Tx-M), and PGI(2), 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.
引用
收藏
页码:334 / 342
页数:9
相关论文
共 50 条
  • [2] Thromboxane A2 receptor antagonism and selective inhibition of cyclooxygenase 2 in atherosclerosis
    Egan, KM
    Wang, M
    Lucitt, M
    Lawson, J
    FitzGerald, GA
    CIRCULATION, 2004, 110 (17) : 177 - 177
  • [3] Cyclooxygenase-2 inhibition and thromboxane A2 receptor antagonism attenuate hypoxic pulmonary vasoconstriction in a porcine model
    Kylhammar, D.
    Radegran, G.
    ACTA PHYSIOLOGICA, 2012, 205 (04) : 507 - 519
  • [4] DIBENZOXEPIN DERIVATIVES - THROMBOXANE-A(2) SYNTHASE INHIBITION AND THROMBOXANE A(2)-RECEPTOR ANTAGONISM COMBINED IN ONE MOLECULE
    OHSHIMA, E
    SATO, H
    OBASE, H
    MIKI, I
    ISHII, A
    KAWAKAGE, M
    SHIRAKURA, S
    KARASAWA, A
    KUBO, K
    JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (11) : 1613 - 1618
  • [5] EFFECTS OF COMBINED THROMBOXANE SYNTHETASE INHIBITION THROMBOXANE RECEPTOR ANTAGONISM IN 2 MODELS OF SUDDEN CARDIAC DEATH IN THE CANINE - LIMITED ROLE FOR THROMBOXANE
    KITZEN, JM
    CHI, LG
    UPRICHARD, ACG
    LUCCHESI, BR
    JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1990, 16 (01) : 68 - 80
  • [6] ROLE OF PROAGGREGATORY AND ANTIAGGREGATORY PROSTAGLANDINS IN HEMOSTASIS - STUDIES WITH COMBINED THROMBOXANE SYNTHASE INHIBITION AND THROMBOXANE RECEPTOR ANTAGONISM
    GRESELE, P
    ARNOUT, J
    DECKMYN, H
    HUYBRECHTS, E
    PIETERS, G
    VERMYLEN, J
    JOURNAL OF CLINICAL INVESTIGATION, 1987, 80 (05): : 1435 - 1445
  • [7] THROMBOXANE RECEPTOR ANTAGONISM COMBINED WITH THROMBOXANE SYNTHASE INHIBITION .1. (+/-)-(3-PYRIDINYLBICYCLOHEPTYL)ALKANOIC ACIDS
    BHAGWAT, SS
    GUDE, C
    COHEN, DS
    LEE, W
    FURNESS, P
    CLARKE, FH
    JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (06) : 1790 - 1797
  • [8] THROMBOXANE RECEPTOR ANTAGONISM COMBINED WITH THROMBOXANE SYNTHASE INHIBITION .7. PYRIDINYLALKYL-SUBSTITUTED ARYLSULFONYLAMINO ARYLALKANOIC ACIDS
    BHAGWAT, SS
    ROLAND, DM
    MAIN, AJ
    GUDE, C
    GRIM, K
    GOLDSTEIN, R
    COHEN, DS
    DOTSON, R
    MATHIS, J
    LEE, W
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1992, 2 (12) : 1623 - 1626
  • [9] Terbogrel, a dual-acting agent for thromboxane receptor antagonism and thromboxane synthase inhibition
    Michaux, C
    Norberg, B
    Dogné, JM
    Durant, F
    Masereel, B
    Delarge, J
    Wouters, J
    ACTA CRYSTALLOGRAPHICA SECTION C-CRYSTAL STRUCTURE COMMUNICATIONS, 2000, 56 (56) : 1265 - 1266
  • [10] THROMBOXANE SYNTHASE INHIBITION AND THROMBOXANE-A2 ENDOPEROXIDE RECEPTOR ANTAGONISM IN A CANINE MODEL OF CORONARY-THROMBOSIS
    FITZGERALD, D
    FRAGETTA, J
    FITZGERALD, GA
    CIRCULATION, 1985, 72 (04) : 422 - 422