Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice.
Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice.
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DOI：
10.1172/jci21446
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Takuya Kobayashi;Y. Tahara;Mayumi Matsumoto;M. Iguchi;H. Sano;T. Murayama;H. Arai;H. Oida;
中科院分区：
文献类型：
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作者：
Takuya Kobayashi;Y. Tahara;Mayumi Matsumoto;M. Iguchi;H. Sano;T. Murayama;H. Arai;H. Oida;
动脉粥样硬化患者体内血栓素 (TX) A2 和 PG I2/前列环素 (PGI2) 的产生增加。然而，它们在动脉粥样硬化形成中的作用尚未得到严格定义。为了研究这个问题，我们将易患动脉粥样硬化的 apoE 缺陷小鼠与缺乏 TXA 受体 (TP) 或 PGI 受体 (IP) 的小鼠进行杂交。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，但与单独缺乏apoE的小鼠相比，apoE-/-TP-/-小鼠表现出动脉粥样硬化形成显着延迟，而apoE-/-IP-/-小鼠表现出动脉粥样硬化显着加速。与apoE-/-TP-/-小鼠相比，apoE-/-IP-/-小鼠的斑块显示出部分内皮破坏，并且上覆内皮细胞中ICAM-1表达增强，血小板内皮细胞粘附分子1（PECAM-1）表达减少。离体凝血酶活化血小板显示，与 apoE-/- 小鼠相比，apoE-/-IP-/- 和 apoE-/-TP-/- 小鼠的血小板对表面 P-选择素表达的敏感性分别较高和较低。颈总动脉的活体显微镜检查显示，apoE-/-IP-/- 小鼠血管壁上滚动的白细胞数量明显多于 apoE-/-TP-/- 或 apoE-/- 小鼠。我们得出的结论是，TXA2 通过控制血小板活化和白细胞-内皮细胞相互作用，促进动脉粥样硬化形成的起始和进展，而 PGI2 则阻止动脉粥样硬化形成的起始和进展。
Production of thromboxane (TX) A2 and PG I2/prostacyclin (PGI2) 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 TXA2 promotes and PGI2 prevents the initiation and progression of atherogenesis through control of platelet activation and leukocyte-endothelial cell interaction.