Department of Emergency and Critical Care Medicine, School of Medicine, Keio University, Tokyo, Japan
Circulation. 2012 Dec 18;126(25):3070-80. doi: 10.1161/CIRCULATIONAHA.112.097097. Epub 2012 Nov 6.
Acute aortic dissection (AAD) is a life-threatening vascular disease without effective pharmaceutical therapy. Matrix metalloproteinases (MMPs) are implicated in the development of chronic vascular diseases including aneurysm, but the key effectors and mechanism of action remain unknown. To define further the role of MMPs in AAD, we screened circulating MMPs in AAD patients, and then generated a novel mouse model for AAD to characterize the mechanism of action.
MMP9 and angiotensin II were elevated significantly in blood samples from AAD patients than in those from the patients with nonruptured chronic aortic aneurysm or healthy volunteers. Based on the findings, we established a novel AAD model by infusing angiotensin II to immature mice that had been received a lysyl oxidase inhibitor, β-aminopropionitrile monofumarate. AAD was developed successfully in the thoracic aorta by angiotensin II administration to β-aminopropionitrile monofumarate-treated wild-type mice, with an incidence of 20%, 80%, and 100% after 6, 12, and 24 hours, respectively. Neutrophil infiltrations were observed in the intima of the thoracic aorta, and the overexpression of MMP9 in the aorta was demonstrated by reverse transcription polymerase chain reaction, gelatin zymography, and immunohistochemistry. The incidence of AAD was reduced significantly by 40% following the administration of an MMP inhibitor and was almost blocked completely in MMP(-/-) mice without any influence on neutrophil infiltration. Neutrophil depletion by injection of anti-granulocyte-differentiation antigen-1 (anti-Gr-1) antibody also significantly decreased the incidence of AAD.
These data suggest that AAD is initiated by neutrophils that have infiltrated the aortic intima and released MMP9 in response to angiotensin II.
急性主动脉夹层（AAD）是一种危及生命的血管疾病，目前尚无有效的药物治疗方法。基质金属蛋白酶（MMPs）与包括动脉瘤在内的慢性血管疾病的发生发展有关，但关键的效应因子和作用机制仍不清楚。为了进一步明确 MMPs 在 AAD 中的作用，我们筛选了 AAD 患者的循环 MMPs，然后构建了一种新型 AAD 小鼠模型以阐明其作用机制。
AAD 患者的血液样本中 MMP9 和血管紧张素 II 显著升高，高于非破裂性慢性主动脉瘤患者或健康志愿者的血液样本。基于这些发现，我们通过向接受赖氨酸氧化酶抑制剂 β-氨基丙腈单富马酸盐处理的幼鼠输注血管紧张素 II 建立了一种新型 AAD 模型。血管紧张素 II 给药可成功地在 β-氨基丙腈单富马酸盐处理的野生型小鼠的胸主动脉中诱发 AAD，6、12 和 24 小时后分别有 20%、80%和 100%的小鼠发病。胸主动脉内膜中有中性粒细胞浸润，逆转录聚合酶链反应、明胶酶谱和免疫组化显示 MMP9 在主动脉中的表达上调。MMP 抑制剂的给药可使 AAD 的发生率显著降低 40%，而 MMP(-/-) 小鼠的 AAD 发生率几乎完全被阻断，且对中性粒细胞浸润无任何影响。注射抗粒细胞分化抗原-1（抗-Gr-1）抗体耗竭中性粒细胞也可显著降低 AAD 的发生率。
这些数据表明，AAD 是由浸润主动脉内膜的中性粒细胞引发的，这些中性粒细胞在血管紧张素 II 的作用下释放 MMP9。
