Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice
Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice
复制标题
DOI：
10.1172/jci200421446
复制
发表时间：
2004-09-01
影响因子：
15.9
通讯作者：
Narumiya, S
中科院分区：
文献类型：
--
作者：
Kobayashi, T;Tahara, Y;Narumiya, S
动脉粥样硬化患者血栓烷(TX)A(2)和前列环素(2)/前列环素(PGI(2))的产生增加。然而，它们在动脉粥样硬化形成中的作用还没有得到严格的定义。为了研究这个问题，我们将易患动脉粥样硬化的载脂蛋白E缺陷小鼠与缺乏血栓素A受体(TP)或前列环素受体(IP)的小鼠杂交。尽管它们的血清胆固醇和甘油三酯水平与apoE缺陷小鼠相似，但apoE(-/-)TP(-/-)小鼠在动脉粥样硬化形成方面表现出显著的延迟，而apoE(-/-)IP(-/-)小鼠与单独缺乏apoE的小鼠相比，动脉粥样硬化的形成显著加速。与apoE(-/-)TP(-/-)小鼠相比，apoE(-/-)IP(-/-)小鼠的斑块表现为部分内皮细胞破坏，内皮细胞ICAM-1表达增强，血小板内皮细胞黏附分子-1(PECAM-1)表达降低。体外凝血酶激活对apoE(-/-)IP(-/-)和apoE(-/-)TP(-/-)小鼠血小板表面P-选择素表达的敏感性分别高于apoE(-/-)和TP(-/-)小鼠。颈总动脉活体显微镜显示apoE(-/-)IP(-/-)小鼠的血管壁上滚动的白细胞数量显著多于apoE(-/-)TP(-/-)或apoE(-/-)小鼠。我们得出结论：TXA(2)促进动脉粥样硬化的发生和发展，而PGI(2)则通过控制血小板活化和白细胞与内皮细胞的相互作用来预防动脉粥样硬化的发生和发展。
Production of thromboxane (TX) A(2) and PGI(2)/prostacyclin (PGI(2)) is increased in patients with atherosclerosis. However, their roles in atherogenesis have not been critically defined. To examine this issue, we cross-bred atherosclerosis-prone apoE-deficient mice with mice deficient in either the TXA receptor (TP) or the PGI receptor (IP). Although they showed levels of serum cholesterol and triglyceride similar to those of apoE-deficient mice, apoE(-/-)TP(-/-) mice exhibited a significant delay in atherogenesis, and apoE(-/-)IP(-/-) mice exhibited a significant acceleration in atherogenesis compared with mice deficient in apoE alone. The plaques in apoE(-/-)IP(-/-) mice showed partial endothelial disruption and exhibited enhanced expression of ICAM-1 and decreased expression of platelet endothelial cell adhesion molecule 1 (PECAM-1) in the overlying endothelial cells compared with those of apoE(-/-)TP(-/-) mice. Platelet activation with thrombin ex vivo revealed higher and lower sensitivity for surface P-selectin expression in platelets of apoE(-/-)IP(-/-) and apoE(-/-)TP(-/-) mice, respectively, than in those of apoE(-/-) mice. Intravital microscopy of the common carotid artery revealed a significantly greater number of leukocytes rolling on the vessel walls in apoE(-/-)IP(-/-) mice than in either apoE(-/-)TP(-/-) or apoE(-/-) mice. We conclude that TXA(2) promotes and PGI(2) prevents the initiation and progression of atherogenesis through control of platelet activation and leukocyte-endothelial cell interaction.