Thromboxane receptor blockade improves the antiatherogenic effect of thromboxane A2 suppression in LDLR KO mice.
Suppression of thromboxane (Tx) A(2) biosynthesis retards atherogenesis. In this setting, the coincidental presence of nonconventional ligands for the TxA(2) receptor (TP), such as isoprostanes, could still induce a proatherogenic vascular phenotype. However, no data are available on the effect of combining suppression of TxA(2) formation with blockade of TP in atherogenesis. To this end, we tested the effect of a selective COX-1 inhibitor, SC560, a TP antagonist, BM-573, or a combination of both in low-density lipoprotein receptor-deficient mice on a high-fat diet. None of the treatments affected body weight or plasma cholesterol or triglycerides levels. Although SC-560 suppressed TxA(2) biosynthesis, BM-573 reduced its levels by 35%; in contrast, the 2 drugs, alone or in combination, did not significantly affect prostacyclin levels. At the end of the study, SC560 and BM-573 reduced atherogenesis; however, a further significant decrease was observed in mice receiving both drugs. This effect was associated with a further significant reduction of vascular inflammation, a decrease in macrophages, and an increase in the content of collagen and smooth muscle cells of the atherosclerotic lesions. These results show for the first time that the addition of a TP antagonist increases the antiatherogenic effect of COX-1-dependent TxA(2) suppression.
Cyrus
Tillmann
T
Department of Pharmacology, University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.
Yao
Yuemang
Y
Ding
Tao
T
Dogné
Jean Michel
JM
Praticò
Domenico
D
D000818:Animals; D050197:Atherosclerosis / Q000097:blood* / Q000188:drug therapy; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011973:Receptors, LDL / Q000172:deficiency*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D014657:Vasculitis / Q000097:blood / Q000188:drug therapy
D008565:Membrane Proteins; C475768:N-terbutyl-N'-(2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl)urea; D011720:Pyrazoles; D011973:Receptors, LDL; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C115461:SC 560; D013453:Sulfonylurea Compounds; D014280:Triglycerides; D013928:Thromboxane A2; D003094:Collagen; D002784:Cholesterol; D011464:Epoprostenol; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse