Inhibition of the mTOR pathway in abdominal aortic aneurysm: implications of smooth muscle cell contractile phenotype, inflammation, and aneurysm expansion
Inhibition of the mTOR pathway in abdominal aortic aneurysm: implications of smooth muscle cell contractile phenotype, inflammation, and aneurysm expansion
复制标题
腹主动脉瘤中 mTOR 通路的抑制：平滑肌细胞收缩表型、炎症和动脉瘤扩张的影响
DOI：
10.1152/ajpheart.00677.2016
复制
发表时间：
2017-06-01
影响因子：
4.8
通讯作者：
Xin, Shijie
中科院分区：
文献类型：
--
作者：
Li, Guangxin;Qin, Lingfeng;Xin, Shijie
腹主动脉瘤（AAA）有效药物治疗的发展可能通过减缓动脉瘤扩张和减少手术需求，为动脉瘤前主动脉扩张患者提供巨大受益。迄今为止，用于减缓主动脉扩张的治疗靶点的疗效较低。因此，在这项研究中，我们的目的是阐明可能的机制驱动动脉瘤进展，以确定潜在的药物干预的目标。我们证明，雷帕霉素（mTOR）信号的机制目标是过度激活的主动脉平滑肌细胞（SMC），这有助于小鼠AAA。雷帕霉素是一种典型的mTOR通路抑制剂，可显著限制腔内弹性蛋白酶灌注后腹主动脉的扩张。此外，通过抑制mTOR途径实现主动脉直径的减小，其保留和/或恢复SMC的收缩表型并下调巨噬细胞浸润、基质金属蛋白酶表达和炎性细胞因子产生。总之，这些结果突出了mTOR级联在动脉瘤进展中的重要作用以及雷帕霉素作为AAA治疗候选药物的潜在应用。新&值得注意的是这项研究提供了新的观察结果，即雷帕霉素（mTOR）信号传导的机制靶点在主动脉平滑肌细胞中过度激活，并导致小鼠腹主动脉瘤（AAA），雷帕霉素可防止动脉瘤的发展。我们的数据强调了AAA中平滑肌细胞收缩表型的保存和/或恢复以及通过mTOR抑制减少炎症的重要性。
The development of effective pharmacological treatment of abdominal aortic aneurysm (AAA) potentially offers great benefit to patients with preaneurysmal aortic dilation by slowing the expansion of aneurysms and reducing the need for surgery. To date, therapeutic targets for slowing aortic dilation have had low efficacy. Thus, in this study, we aim to elucidate possible mechanisms driving aneurysm progression to identify potential targets for pharmacological intervention. We demonstrate that mechanistic target of rapamycin (mTOR) signaling is overactivated in aortic smooth muscle cells (SMCs), which contributes to murine AAA. Rapamycin, a typical mTOR pathway inhibitor, dramatically limits the expansion of the abdominal aorta following intraluminal elastase perfusion. Furthermore, reduction of aortic diameter is achieved by inhibition of the mTOR pathway, which preserves and/or restores the contractile phenotype of SMCs and downregulates macrophage infiltration, matrix metalloproteinase expression, and inflammatory cytokine production. Taken together, these results highlight the important role of the mTOR cascade in aneurysm progression and the potential application of rapamycin as a therapeutic candidate for AAA.NEW & NOTEWORTHY This study provides novel observations that mechanistic target of rapamycin (mTOR) signaling is overactivated in aortic smooth muscle cells and contributes to mouse abdominal aortic aneurysm (AAA) and that rapamycin protects against aneurysm development. Our data highlight the importance of preservation and/or restoration of the smooth muscle cell contractile phenotype and reduction of inflammation by mTOR inhibition in AAA.