Additive anti-atherogenic effect of thromboxane receptor antagonism with 12/15lipoxygenase gene disruption in apolipoprotein E-deficient mice.
Previous studies in mouse models showed that 12/15lipoxygenase (12/15LO) gene disruption diminishes atherosclerosis. Pharmacologic suppression of thromboxane (Tx) A(2) biosynthesis or blockade of its receptor also reduces the development of the disease in the same models. We tested the hypothesis that simultaneous genetic absence of 12/15LO with TxA(2) receptor blockade might result in an additive anti-atherogenic effect. Apolipoprotein E (apoE)-deficient mice and apoE-deficient mice lacking 12/15LO were maintained on normal chow diet, or chow supplemented with BM-573, a selective TxA(2) receptor antagonist, for 12 weeks. Urinary TxA(2) and prostacyclin metabolites, isoprostaneF(2*)-III and atherosclerotic aortic lesions were assessed. 12/15LO gene disruption resulted in significantly reduced atherosclerotic lesion areas and decreased urinary isoprostaneF(2*)-III in apoE-deficient mice. TxA(2) receptor antagonism alone also afforded a significant reduction in atherosclerosis in apoE-deficient mice. However, thromboxane receptor blockade resulted in an additive and more potent anti-inflammatory and anti-atherogenic effect when administered to apoE-deficient mice lacking 12/15LO. These results suggest that the 12/15LO- and TxA(2) receptor-mediated pro-atherogenic effects are two distinct pathways and represent two separate therapeutic targets for a better anti-atherogenic strategy.
Tang
Liung
L
Department of Pharmacology, School of Medicine, Temple University, Philadelphia, PA 19140, United States.
Ding
Tao
T
Praticò
Domenico
D
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism*; D005786:Gene Expression Regulation; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013927:Thrombosis; D013928:Thromboxane A2 / Q000378:metabolism; D014810:Vitamin E / Q000378:metabolism
C475064:12-15-lipoxygenase; D000975:Antioxidants; D001057:Apolipoproteins E; D017482:Receptors, Thromboxane; D014810:Vitamin E; D013928:Thromboxane A2; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase