The thromboxane A2 receptor antagonist S18886 prevents enhanced atherogenesis caused by diabetes mellitus.
BACKGROUND
S18886 is an orally active thromboxane A2 (TXA2) receptor (TP) antagonist in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. We previously showed that S18886 inhibits atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice by a mechanism independent of platelet-derived TXA2. Atherosclerosis is accelerated by diabetes and is associated with increased TXA(2) and other eicosanoids that stimulate TP. The purpose of this study was to determine whether S18886 lessens the enhanced atherogenesis in diabetic apoE(-/-) mice.


RESULTS
Diabetes mellitus was induced in apoE(-/-) mice with streptozotocin and was treated or not with S18886 (5 mg.kg(-1).d(-1)). After 6 weeks, aortic lesion area was increased >4-fold by diabetes in apoE(-/-) mice, associated with similar increases in serum glucose and cholesterol. S18886 largely prevented the diabetes-related increase in lesion area without affecting the hyperglycemia or hypercholesterolemia. S18886 prevented deterioration of endothelial function and endothelial nitric oxide synthase expression, as well as increases in intimal markers of inflammation associated with diabetes. In human aortic endothelial cells in culture, S18886 also prevented the induction of vascular cell adhesion molecule-1 and prevented the decrease in endothelial nitric oxide synthase expression caused by high glucose.


CONCLUSIONS
The TP antagonist inhibits inflammation and accelerated atherogenesis caused by diabetes, most likely by counteracting effects on endothelial function and adhesion molecule expression of eicosanoids stimulated by the diabetic milieu.
Zuccollo
Adriana
A
Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Shi
Chaomei
C
Mastroianni
Roberto
R
Maitland-Toolan
Karlene A
KA
Weisbrod
Robert M
RM
Zang
Mengwei
M
Xu
Shanqin
S
Jiang
Bingbing
B
Oliver-Krasinski
Jennifer M
JM
Cayatte
Antonio J
AJ
Corda
Stefano
S
Lavielle
Gilbert
G
Verbeuren
Tony J
TJ
Cohen
Richard A
RA
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000517:prevention & control*; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*
D001057:Apolipoproteins E; D009281:Naphthalenes; D011422:Propionates; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C501362:terutroban