Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice
Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice
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DOI：
10.1161/01.cir.0000014927.74465.7f
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发表时间：
2002-04-16
期刊：
影响因子：
37.8
通讯作者：
Linton, MF
中科院分区：
文献类型：
--
作者：
Burleigh, ME;Babaev, VR;Linton, MF
背景：动脉粥样硬化具有炎症性疾病的特征，由于环氧化酶(COX)-2在动脉粥样硬化病变中表达并促进炎症，我们验证了选择性抑制COX-2可减少LDL受体缺陷（LDLR-/-）小鼠早期病变形成的假设，以及巨噬细胞COX-2表达有助于LDLR-/-小鼠动脉粥样硬化的假设。方法与结果：雄性LDLR-/-小鼠给予罗非昔布或吲哚美辛治疗6周后，近端主动脉动脉粥样硬化（25%和37%）和侧主动脉动脉粥样硬化（58%和57%）分别显著降低。罗非昔布治疗不抑制血小板血栓素的产生（cox -1介导的过程），但显著降低尿前列环素代谢物2,3-dinor-6-keto- pgf （1 α）。采用胎儿肝细胞移植，通过巨噬培养COX-2基因表达缺失的LDLR-/-小鼠。在西方饮食8周后，COX-2(-/-)- >LDLR-/-小鼠的动脉粥样硬化发生率明显低于对照组COX-2(+/+)- >LDLR-/-小鼠（33%至3917c）。在抑制剂研究和移植研究中，两组之间的血脂没有显著差异。结论：目前的研究提供了强有力的药理学和遗传学证据，证明COX-2在体内促进LDLR-/-小鼠动脉粥样硬化病变的形成。这些结果支持了抗炎方法预防动脉粥样硬化的潜力。
Background-Atherosclerosis has features of an inflammatory disease, Because cyclooxygenase (COX)-2 is expressed in atherosclerotic lesions and promotes inflammation, we tested the hypotheses that selective COX-2 inhibition would reduce early lesion formation in LDL receptor-deficient (LDLR-/-) mice and that macrophage COX-2 expression contributes to atherogenesis in LDLR-/- mice.Methods and Results-Treatment of male LDLR-/- mice fed the Western diet with rofecoxib or indomethacin fur 6 weeks resulted in significant reductions in atherosclerosis in the proximal aorta (25% and 37%) and in file aorta en face (58% and 57%), respectively. Rofecoxib treatment did not inhibit platelet thromboxane production, a COX-1-mediated process, but it significantly reduced the urinary prostacyclin metabolite 2,3-dinor-6-keto-PGF(1alpha). Fetal liver cell transplantation was used to generate LDLR-/- mice null for expression of the COX-2 gene by macropliages. After 8 weeks on the Western diet, COX-2(-/-)-->LDLR-/- mice developed significantly less (33% to 3917c) atherosclerosis than control COX-2(+/+)-->LDLR-/- mice. In both the inhibitor studies and the transplant studies, serum lipids did not differ significantly between groups.Conclusions-The present studies provide strong pharmacological and genetic evidence that COX-2 promotes earl), atherosclerotic lesion formation in LDLR-/- mice in vivo. These results support the potential of anti-inflamminatory approaches to the prevention of atherosclerosis.