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(Circulation. 2005;111:334-342.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Cyclooxygenases, Thromboxane, and Atherosclerosis

Plaque Destabilization by Cyclooxygenase-2 Inhibition Combined With Thromboxane Receptor Antagonism

Karine M. Egan, PhD; Miao Wang, PhD; Margaret B. Lucitt, BSc; Alicia M. Zukas, AB; Ellen Puré, PhD; John A. Lawson, MS; Garret A. FitzGerald, MD

From the Institute for Translational Medicine and Therapeutics (K.M.E., M.W., M.B.L., J.A.L., G.A.F.), University of Pennsylvania, Philadelphia, Pa, The Wistar Institute and The Ludwig Institute for Cancer Research (A.M.Z., E.P.), Philadelphia, Pa.

Correspondence to Garret A. FitzGerald, MD, 153 Johnson Pavilion, University of Pennsylvania, Philadelphia, PA 19104. E-mail garret{at}spirit.gcrc.upenn.edu

Received June 29, 2004; revision received October 28, 2004; accepted November 3, 2004.

Background— Antagonism or deletion of the receptor (the TP) for the cyclooxygenase (COX) product thromboxane (Tx)A₂, 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) I₂ and PGE₂, may both promote inflammation and restrain the effects of TxA₂. 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 TxA₂, 2,3-dinor TxB₂ (Tx-M), and PGI₂, 2,3-dinor 6-keto PGF₁ (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-iPF₂-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.

Key Words: thromboxane • atherosclerosis • lesion • prostaglandins • inflammation

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