Essential Role of Angiotensin II Type 1a Receptors in the Host Vascular Wall, but Not the Bone Marrow, in the Pathogenesis of Angiotensin II-Induced Atherosclerosis
Essential Role of Angiotensin II Type 1a Receptors in the Host Vascular Wall, but Not the Bone Marrow, in the Pathogenesis of Angiotensin II-Induced Atherosclerosis
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DOI：
10.1291/hypres.31.1791
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发表时间：
2008-09-01
影响因子：
5.4
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Kogai, Jun-ichiro;Egashira, Kensuke;Sunagawa, Kenji
血管紧张素II（AngII）1a型（AT 1a）受体在动脉粥样硬化病变的多种细胞类型上表达，包括骨髓源性细胞和血管壁细胞，并介导炎症和增殖反应。事实上，血管紧张素II输注通过募集单核细胞和激活血管壁细胞加速高血压小鼠的动脉粥样硬化形成。在此，我们研究了血管紧张素II诱导的动脉粥样硬化形成中骨髓与血管壁中AT 1a受体的相对作用。通过使用ATI 1a（+/+）或ATIa（-/-）受体的实验性骨髓移植产生具有或不具有骨髓AT 1a受体的载脂蛋白E敲除（ApoE（-/-））小鼠。在这些小鼠中，28天的血管紧张素II输注诱导显着的动脉粥样硬化的主动脉，斑块形成的严重程度不受骨髓AT 1a受体的缺乏。然后我们产生了有或没有骨髓AT 1a受体的AT 1a（-/-）ApoE（-/-）小鼠。血管紧张素II诱导的斑块形成是钝的，无论是否存在骨髓AT 1a受体。发现宿主AT 1a受体缺陷抑制Ang II诱导的活性氧产生。此外，AT 1a受体缺陷也损害单核细胞趋化蛋白-1（MCP-1）和血管细胞粘附分子-1（VCAM-1）在血管紧张素11启动后7天在动脉壁的表达。这些分子通常在血管壁中引发巨噬细胞介导的炎症。相比之下，骨髓中AT 1a受体缺乏并不影响MCIP-1诱导的单核细胞体外趋化性。总之，AT 1a受体在宿主血管壁，而不是在骨髓中，是必不可少的血管紧张素II诱导的动脉粥样硬化形成。（Hypertens Res 2008; 31：1791-1800）
The angiotensin II (Ang II) type 1a (AT1a) receptor is expressed on multiple cell types In atherosclerotic lesions, including bone marrow-derived cells and vascular wall cells, and mediates inflammatory and proliferative responses. Indeed, Ang II infusion accelerates atherogenesis in hyperlipidemic mice by recruiting monocytes and by activating vascular wall cells. Here, we investigated the relative roles of AT1a receptors in the bone marrow vs. the vascular wall in Ang II-induced atherogenesis. Apolipoprotein E-knockout (ApoE(-/-)) mice with or without bone marrow AT1a receptor were generated by experimental bone marrow transplantation using ATI1a(+/+), or ATIa(-/-) recipients. In these mice, 28-d Ang II infusion induced significant atherosclerosis in the aorta, and the severity of plaque formation was not affected by the absence of bone marrow AT1a receptor. We then generated AT1a(-/-)ApoE(-/-) mice with or without bone marrow AT1a receptor. Ang II-induced plaque formation was blunted irrespective of the presence of bone marrow AT1a receptor. Host AT1a receptor deficiency was found to suppress Ang II-induced reactive oxygen species production. In addition, AT1a receptor deficiency also impaired monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in the arterial wall 7 d after Ang 11 initiation. These molecules normally initiate later macrophage-mediated inflammation in the vascular wall. By contrast, AT1a receptor deficiency in the bone marrow did not affect MCIP-1-induced monocyte chemotaxis in vitro. In conclusion, AT1a receptors in the host vascular wall, but not in the bone marrow, are essential in Ang II-induced atherogenesis. (Hypertens Res 2008; 31: 1791-1800)