β2 integrins modulate the initiation and progression of atherosclerosis in low-density lipoprotein receptor knockout mice
β2 integrins modulate the initiation and progression of atherosclerosis in low-density lipoprotein receptor knockout mice
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DOI：
10.1093/cvr/cvp347
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发表时间：
2010-03-01
影响因子：
10.8
通讯作者：
Chan, Lawrence
中科院分区：
文献类型：
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作者：
Merched, Aksam;Tollefson, Katherine;Chan, Lawrence
β2整合素介导的黏附被认为是心血管疾病的关键事件。然而，针对这些分子的临床试验结果令人失望。在这里，我们研究了CD18(-/-)细胞在低密度脂蛋白受体基因敲除(LDLR(-/-))小鼠体内的定时骨髓移植(BMT)在动脉粥样硬化不同阶段对β2整合素失活的影响。在脂肪条纹形成之前的早期BMT显示CD18的短期保护作用(动脉粥样硬化病变减少34%)。一旦在骨髓移植前形成脂肪条纹病变(5周致动脉粥样硬化饮食)，β2整合素的表达不会影响病变进展。然而，在建立更成熟的病变(预先喂养致动脉粥样硬化饮食10周的小鼠)后，与CD18(-/-)BMT相比，CD18(+/+)BMT促进了动脉粥样硬化(36%)的病变进展。此外，β2整合素调节分离的腹膜巨噬细胞摄取乙酰化的低密度脂蛋白和天然低密度脂蛋白的能力，以及吞噬凋亡细胞的能力，可能是通过CD18依赖的丝裂原激活的蛋白激酶信号。CD18(-/-)和CD18(+/+)巨噬细胞的基因表达谱显示，CD18(-/-)和CD18(+/+)巨噬细胞在保护和致动脉粥样硬化方面存在显著差异。β2整合素介导的白细胞与血管壁的相互作用是一个时间依赖的动态过程。在起始阶段，它可以防止动脉粥样硬化病变的形成。然而，随着病变的演变和长期暴露于血脂异常，β2整合素的促动脉粥样硬化作用变得主导，加速了动脉粥样硬化的进程。
beta 2 integrin-mediated adhesion is thought to be a key event in cardiovascular disease. However, results of clinical trials targeting these molecules have been disappointing. Here, we investigated the effect of inactivation of beta 2 integrins at different stages of atherosclerosis by timed bone marrow transplantation (BMT) of CD18(-/-) cells in low-density lipoprotein receptor knockout (LDLR(-/-)) mice.Early BMT before fatty streak formation revealed a short-term protective effect of CD18 (34% atherosclerotic lesion reduction). Once fatty streak lesions had developed (5-week atherogenic diet) before BMT, beta 2 integrin expression did not affect lesion progression. However, after the establishment of more mature lesions (pre-feeding mice the atherogenic diet for 10 weeks), CD18(+/+) BMT enhanced atherosclerosis (36%) lesion progression compared with CD18(-/-) BMT. Furthermore, beta 2 integrins modulated the capacity of isolated peritoneal macrophages to take up acetylated LDL and native LDL and to phagocytose apoptotic cells, possibly via CD18-dependent mitogen-activated protein kinase signalling. Gene expression profile of CD18(-/-) and CD18(+/+) macrophages revealed significant differences in putative protective as well as atherogenic functions.beta 2 integrin-mediated interaction between leucocytes and the vessel wall is a time-dependent and dynamic process. During the initiation phase, it protects against atherosclerotic lesion formation. However, with the evolution of the lesion and chronic exposure to dyslipidaemia, beta 2 integrins' pro-atherogenic action becomes dominant, accelerating the atherosclerotic process.