Effects of Caspase Inhibitor on Angiotensin II-Induced Abdominal Aortic Aneurysm in Apolipoprotein E-Deficient Mice
Effects of Caspase Inhibitor on Angiotensin II-Induced Abdominal Aortic Aneurysm in Apolipoprotein E-Deficient Mice
复制标题
DOI：
10.1161/atvbaha.109.200527
复制
发表时间：
2010-04-01
影响因子：
8.7
通讯作者：
Liu, Bo
中科院分区：
文献类型：
--
作者：
Yamanouchi, Dai;Morgan, Stephanie;Liu, Bo
凋亡标志物的存在是腹主动脉瘤的一个突出的组织学特征。为了了解细胞凋亡在这种常见的血管疾病的发病机制中的作用，我们测试了泛半胱天冬酶抑制剂喹啉-缬氨酸-天冬氨酸-二氟苯氧基甲基酮（Q-VD-OPh）对动脉瘤形成的影响，使用小鼠血管紧张素II（Ang II）model.Methods和Results-Ang II在载脂蛋白E缺陷小鼠中显着诱导中膜细胞凋亡3天后，在主动脉区域输注，最终成为血管紧张素II。在Ang II输注前6小时开始每天给予20 mg/kg Q-VD-OPh，使动脉瘤发生率从83.3%降至16.7%，最大主动脉直径从2.43 +/- 0.29 mm降至1.58 +/- 0.18 mm。半胱天冬酶抑制剂治疗的小鼠显示中膜细胞凋亡和炎症水平显著降低。相比之下，在Ang II输注后7天开始给予Q-VD-OPh对动脉瘤的发展没有显著影响。在体外，条件培养基血管紧张素II处理的平滑肌细胞（SMCs）刺激巨噬细胞的趋化性在半胱天冬酶依赖的方式。抑制单核细胞趋化蛋白-1（MCP-1）在条件培养基中通过中和抗体完全阻断了条件培养基的能力，以吸引macrophage. Conclusion这些结果表明，中膜SMC凋亡可能有助于血管炎症，从而动脉瘤的形成，部分通过生产MCP-1。（Arterioscler Thromb Vasc Biol.2010; 30：702-707.）
Objective-The presence of apoptotic markers is a prominent histological feature of abdominal aortic aneurysm. To understand the role of apoptosis in the pathogenesis of this common vascular disease, we tested the effect of the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone (Q-VD-OPh) on aneurysm formation using a mouse angiotensin II (Ang II) model.Methods and Results-Ang II in apolipoprotein E-deficient mice significantly induced medial cell apoptosis 3 days after infusion at the aortic region, eventually becoming aneurismal. A daily administration of 20 mg/kg per day Q-VD-OPh starting 6 hours before Ang II infusion reduced aneurysm incidence from 83.3% to 16.7% and maximal aortic diameter from 2.43 +/- 0.29 mm to 1.58 +/- 0.18 mm. The caspase inhibitor treated mice showed profoundly diminished levels of medial apoptosis and inflammation. In contrast, administration of Q-VD-OPh starting 7 days after Ang II infusion had no significant impact on aneurysm development. In vitro, media conditioned by Ang II-treated smooth muscle cells (SMCs) stimulated macrophage chemotaxis in a caspase-dependent manner. Inhibition of monocyte chemoattractant protein-1 (MCP-1) in the conditioned media via a neutralizing antibody completely blocked the ability of conditioned media to attract macrophages.Conclusion-These results indicate that medial SMC apoptosis may contribute to vascular inflammation and thus aneurysm formation, in part through production of MCP-1. (Arterioscler Thromb Vasc Biol. 2010; 30: 702-707.)