Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice
Angiotensin II-accelerated atherosclerosis and aneurysm formation is attenuated in osteopontin-deficient mice
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DOI：
10.1172/jci200318141
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发表时间：
2003-11-01
影响因子：
15.9
通讯作者：
Hsueh, WA
中科院分区：
文献类型：
--
作者：
Bruemmer, D;Collins, AR;Hsueh, WA
骨桥蛋白（OPN）在动脉粥样硬化病变中表达，特别是在糖尿病患者中。为了确定OPN在动脉粥样硬化形成中的作用，ApoE(-/-)OPN(+/+)、ApoE(-/-)OPN(+/-)和ApoE(-/-)OPN(-/-)小鼠被注射Ang II，诱导血管CPN表达并加速动脉粥样硬化。与ApoE(-/-)OPN(+/+)小鼠相比，ApoE(-/-)OPN(+/-)和ApoE(-/-)OPN(-/-)小鼠发生Ang II加速动脉粥样硬化的情况较少。与接受 ApoE(-/-)OPN(+/+) 细胞的动物相比，移植 ApoE(-/-)OPN(-/-) 小鼠骨髓的 ApoE(-/-) 小鼠具有较少的 Ang II 诱导的动脉粥样硬化。 Ang II 输注 ApoE(-/-)OPN(-/-) 小鼠的主动脉表达较少的 CD68、C-C 趋化因子受体 2 和 VCAM-1。 OPN-/-小鼠中的白细胞对腹膜内硫代乙醇酸盐的募集受到损害，并且OPN-/-白细胞表现出基础迁移和MCP-1定向迁移减少。此外，注入 Ang II 的 ApoE(-/-)OPN(-/-) 小鼠动脉粥样硬化病变中的巨噬细胞活力降低。最后，Ang II 诱导的 ApoE(-/-O)PN(-/-) 小鼠腹主动脉瘤形成减少，并与 MMP-2 和 MMP-9 活性降低相关。这些数据表明白细胞源性 OPN 在介导 Ang II 加速动脉粥样硬化和动脉瘤形成中发挥重要作用。
Osteopontin (OPN) is expressed in atherosclerotic lesions, particularly in diabetic patients. To determine the role of OPN in atherogenesis, ApoE(-/-)OPN(+/+), ApoE(-/-)OPN(+/-), and ApoE(-/-)OPN(-/-) mice were infused with Ang II, inducing vascular CPN expression and accelerating atherosclerosis. Compared with ApoE(-/-)OPN(+/+) mice, ApoE(-/-)OPN(+/-) and ApoE(-/-)OPN(-/-) mice developed less Ang II-accelerated atherosclerosis. ApoE(-/-) mice transplanted with bone marrow derived from ApoE(-/-)OPN(-/-) mice had less Ang II-induced atherosclerosis compared with animals receiving ApoE(-/-)OPN(+/+) cells. Aortae from Ang II-infused ApoE(-/-)OPN(-/-) mice expressed less CD68, C-C-chemokine receptor 2, and VCAM-1. In response to intraperitoneal thioglycollate recruitment of leukocytes in OPN-/- mice was impaired, and OPN-/- leukocytes exhibited decreased basal and MCP-1-directed migration. Furthermore, macrophage viability in atherosclerotic lesions from Ang II-infused ApoE(-/-)OPN(-/-) mice was decreased. Finally, Ang II-induced abdominal aortic aneurysm formation in ApoE(-/-O)PN(-/-) mice was reduced and associated with decreased MMP-2 and MMP-9 activity. These data suggest an important role for leukocytederived OPN in mediating Ang II-accelerated atherosclerosis and aneurysm formation.