Suppression of foam cell lesions in hypercholesterolemic rabbits by inhibition of thromboxane A2 synthesis.
Hypercholesterolemia induces adhesion of blood-borne monocytes to vascular endothelium and their subsequent migration into the intima, where foam cell lesions subsequently develop. The regulating mechanisms for the adhesion and migration are unclear. In this study, a specific thromboxane A2 (TXA2) synthetase inhibitor, UK-38485, was used to treat rabbits fed an atherogenic diet to determine whether inhibition of TXA2, the major metabolite of arachidonic acid in monocytes, affects lesion development. Rabbits were fed a diet supplemented with 2% cholesterol and 8% peanut oil for 12 weeks with or without UK-38485 at a dosage that maintained 80% to 90% inhibition of TXA2 formation in serum. The treatment with UK-38485 had no effect on total serum cholesterol. Both the treated and untreated groups developed subpopulations of high and low responders with respect to the extent of lesion coverage, forming a bimodal distribution. The treatment with UK-38485 significantly (p less than 0.001) reduced the percentage of the thoracic aorta covered by lesions when treated low responders (5.3 +/- 1.0%, n = 12) were compared to untreated low responders (23.6 +/- 2.9%, n = 12). However, UK-38485 had no effect when treated high responders (76.3%, n = 3) were compared to untreated high responders (72.0%, n = 12). Lesion coverage was not correlated with serum cholesterol levels. Stimulation of isolated rabbit monocytes in autologous plasma with 0.66 mM arachidonic acid in the presence of increasing concentrations of UK-38485 caused a dose-dependent inhibition of TXA2 and a concurrent increase in prostaglandin E2 (PGE2).(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D015232:Dinoprostone; D005487:Foam Cells / Q000473:pathology*; D006937:Hypercholesterolemia / Q000097:blood / Q000473:pathology*; D007093:Imidazoles / Q000494:pharmacology*; D008264:Macrophages / Q000473:pathology*; D008297:Male; D009000:Monocytes / Q000378:metabolism; D011458:Prostaglandins E / Q000096:biosynthesis; D011817:Rabbits; D013928:Thromboxane A2 / Q000096:biosynthesis*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014280:Triglycerides / Q000097:blood
D001095:Arachidonic Acids; D007093:Imidazoles; D011458:Prostaglandins E; D014280:Triglycerides; D016718:Arachidonic Acid; C039242:dazmegrel; D013928:Thromboxane A2; D002784:Cholesterol; D013930:Thromboxane-A Synthase; D015232:Dinoprostone