Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PR China.
Translational Medicine Research Center, Nanjing Medical University, Affiliated Hangzhou Hospital, Hangzhou First People's Hospital, Hangzhou, Zhejiang, 310006, PR China.
Eur J Pharmacol. 2019 Oct 5;860:172559. doi: 10.1016/j.ejphar.2019.172559. Epub 2019 Jul 18.
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 secretion in 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 via in situ assessment 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.
腹主动脉瘤（AAA）的特征是主动脉壁进行性减弱和显著扩张。尽管老年人群的死亡率很高，但目前仍没有临床药理学疗法来缓解 AAA 的进展。巨噬细胞来源的 MMP9 作为细胞外基质降解的关键因素，对于主动脉瘤的发展和主动脉破裂至关重要。在这里，我们证明了在用伊马替尼治疗后，巨噬细胞中的 MMP9 转录水平呈浓度依赖性降低，同时 MMP9 蛋白表达下调，体外 MMP9 分泌减少。伊马替尼给药（50mg/kg/d，ig）在弹性蛋白酶诱导的大鼠 AAA 建立后一周进行，通过降低主动脉直径和防止弹性蛋白降解，稳定动脉瘤的进展并提高存活率。通过免疫组织化学和酶谱等原位评估发现，伊马替尼治疗后 MMP9 在动脉组织中的表达和活性明显受到抑制，尽管巨噬细胞浸润没有受到影响。此外，我们发现伊马替尼通过减少 STAT3 磷酸化和从核到细胞质的转位来抑制 MMP9 的转录。这些观察结果表明，伊马替尼通过抑制 STAT3 介导的 MMP9 表达和激活来预防动脉瘤的进展，提示伊马替尼在 AAA 的临床治疗中有新的应用。
