Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1724-1728
© 2000 American Heart Association, Inc.
Vascular Biology |
The Thromboxane Receptor Antagonist S18886 but Not Aspirin Inhibits Atherogenesis in Apo E–Deficient Mice
Evidence That Eicosanoids Other Than Thromboxane Contribute to Atherosclerosis
From the Vascular Biology Unit (A.J.C., Y.D., J.O.-K., R.A.C.), Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass, and Institut de Recherche Servier (G.L., T.J.V.), Suresnes, France.
Correspondence to Richard A. Cohen, MD, Vascular Biology Unit R408, Boston University Medical Center, 80 E Concord St, Boston, MA 02118. E-mail racohen{at}med-med1.bu.edu
Abstract—Atherosclerosis
involves a complex array of factors, including leukocyte adhesion and
platelet vasoactive factors. Aspirin, which is used to prevent
secondary complications of atherosclerosis, inhibits
platelet production of thromboxane (Tx)
A2. The actions of TxA2 as
well as of other arachidonic acid products, such as
prostaglandin (PG) H2,
PGF2
,
hydroxyeicosatetraenoic acids, and
isoprostanes, can be effectively antagonized by blocking
thromboxane (TP) receptors. The purpose of this study was
to determine the role of platelet-derived
TxA2 in atherosclerotic lesion development by
comparing the effects of aspirin and the TP receptor
antagonist S18886. The effect of 11 weeks of treatment with
aspirin (30 mg · kg-1 ·
d-1) or S18886 (5 mg ·
kg-1 · d-1) on
aortic root atherosclerotic lesions, serum levels of intercellular
adhesion molecule-1 (ICAM-1), and the TxA2
metabolite TxB2 was determined in apolipoprotein
E–deficient mice at 21 weeks of age. Both treatments did not affect
body or heart weight or serum cholesterol levels. Aspirin,
to a greater extent than S18886, significantly decreased serum
TxB2 levels, indicating the greater efficacy of
aspirin in preventing platelet synthesis of
TxA2. S18886, but not aspirin, significantly
decreased aortic root lesions as well as serum ICAM-1 levels. S18886
also prevented the increased expression of ICAM-1 in cultured human
endothelial cells stimulated by the TP receptor agonist
U46619. These results indicate that inhibition of platelet
TxA2 synthesis with aspirin has no significant
effect on atherogenesis or adhesion molecule levels. The effects of
S18886 suggest that blockade of TP receptors inhibits
atherosclerosis by a mechanism independent of
platelet-derived TxA2, perhaps by preventing
the expression of adhesion molecules whose expression is stimulated by
eicosanoids other than TxA2.
Key Words: thromboxane receptor • atherosclerosis • aspirin • adhesion • thromboxane
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