Imatinib prevents elastase-induced abdominal aortic aneurysm progression by regulating macrophage-derived MMP9.
Imatinib prevents elastase-induced abdominal aortic aneurysm progression by regulating macrophage-derived MMP9.
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DOI：
10.1016/j.ejphar.2019.172559
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发表时间：
2019-07
影响因子：
5
通讯作者：
F. Yao;Zhang-ting Yao;Tiecheng Zhong;Jie-qiong Zhang;Ting-ting Wang;Bo Zhang;Qiaojun He;L. Ding
中科院分区：
文献类型：
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作者：
F. Yao;Zhang-ting Yao;Tiecheng Zhong;Jie-qiong Zhang;Ting-ting Wang;Bo Zhang;Qiaojun He;L. Ding
腹主动脉瘤（AAA）的特征是主动脉壁进行性变弱和显著扩张。尽管老年人群的死亡风险较高，但仍然没有缓解AAA进展的临床药理学治疗。巨噬细胞来源的MMP 9作为细胞外基质降解的关键因子，对主动脉瘤的发展和主动脉破裂至关重要。本研究表明，体外实验中伊马替尼可抑制巨噬细胞MMP 9的转录水平，并呈浓度依赖性，同时伴有MMP 9蛋白表达下调和MMP 9分泌减少。伊马替尼给药（50 mg/kg/d，i.g.）在大鼠中建立弹性蛋白酶诱导的AAA后一周进行，通过减小主动脉直径和防止弹性蛋白降解来稳定动脉瘤进展并提高存活率。伊马替尼治疗后，动脉组织中MMP 9的表达和活性显著降低，但巨噬细胞浸润未受影响。此外，我们发现伊马替尼通过减少STAT 3磷酸化和从细胞核到细胞质的易位来抑制MMP 9的转录。这些观察结果表明，伊马替尼通过抑制STAT 3介导的MMP 9表达和活化来预防动脉瘤进展，提示伊马替尼在AAA临床治疗中的新应用。
Abdominal aortic aneurysm (AAA) is characterized with progressive weakening and considerable dilation of the aortic wall. Despite the high risk of mortality in the elderly population, there are still no clinical pharmacological therapies to alleviate AAA progression. Macrophage-derived MMP9 acts as a key factor in extracellular matrix degradation and is crucial for aortic aneurysm development and aortic rupture. Here, we demonstrated that the transcription level of MMP9 was suppressed with a concentration-dependent manner in macrophages after Imatinib treatment, which was accompanied by the down-regulation of MMP9 protein expression and reduced MMP9 secretionin vitro. Imatinib administration (50 mg/kg/d, i.g.) was carried out one week after the establishment of elastase-induced AAA in rats, stabilizing aneurysm progression and improving survival rate via decreasing the aortic diameter and preventing elastin degradation. Expression and activity of MMP9 in the artery tissues were significantly suppressed after Imatinib treatment viain situassessment like immunohistochemistry and zymography, although macrophage infiltration was not affected. Furthermore, we found that Imatinib inhibited MMP9 transcription through reduction of STAT3 phosphorylation and translocation from nucleus to cytoplasm. These observations indicated that Imatinib prevents aneurysm progression by inhibiting STAT3-mediated MMP9 expression and activation, suggesting a new application of Imatinib on AAA clinical therapy.