Luo Hanshen, Wu Xingliang, Huo Bo, Liu Liyuan, Jiang Ding-Sheng, Yi Xin
Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave., Wuhan, 430030, Hubei, China.
Department of Cardiology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, China.
Cell Div. 2023 Aug 9;18(1):13. doi: 10.1186/s13008-023-00096-5.
Aberrant proliferation of vascular smooth muscle cells (VSMCs) is the cause of neointima formation followed by vascular injury. Autophagy is involved in this pathological process, but its function is controversial. Recently, we found that methyltransferase like 3 (METTL3) inhibited VSMC proliferation by activating autophagosome formation. Moreover, we also demonstrated that METTL3 reduced the levels of phosphorylated mammalian target of rapamycin (p-mTOR) and cyclin dependent kinase 1 (p-CDK1/CDC2), which were critical for autophagy and proliferation regulation. However, whether mTOR and CDK1 mediated the function of METTL3 on autophagy and proliferation in VSMCs remains unknown.
We showed that the activator of mTOR, MHY1485 largely reversed the effects of METTL3 overexpression on VSMC autophagy and proliferation. Rapamycin, the inhibitor of mTOR, obviously nullified the pro-proliferation effects of METTL3 knockdown by activating autophagy in VSMCs. Unexpectedly, mTOR did not contribute to the impacts of METTL3 on migration and phenotypic switching of VSMCs. On the other hand, by knockdown of CDK1 in VSMC with METTL3 deficiency, we demonstrated that CDK1 was involved in METTL3-regulated proliferation of VSMCs, but this effect was not mediated by autophagy.
We concluded that mTOR but not CDK1 mediated the role of METTL3 on VSMC proliferation and autophagy.
血管平滑肌细胞（VSMC）的异常增殖是血管损伤后新生内膜形成的原因。自噬参与了这一病理过程，但其功能存在争议。最近，我们发现甲基转移酶样3（METTL3）通过激活自噬体形成来抑制VSMC增殖。此外，我们还证明METTL3降低了对自噬和增殖调节至关重要的磷酸化雷帕霉素靶蛋白（p-mTOR）和细胞周期蛋白依赖性激酶1（p-CDK1/CDC2）的水平。然而，mTOR和CDK1是否介导METTL3对VSMC自噬和增殖的作用仍不清楚。
我们发现mTOR的激活剂MHY1485在很大程度上逆转了METTL3过表达对VSMC自噬和增殖的影响。mTOR的抑制剂雷帕霉素通过激活VSMC中的自噬明显消除了METTL3敲低的促增殖作用。出乎意料的是，mTOR对METTL3对VSMC迁移和表型转换的影响没有作用。另一方面，通过在METTL3缺陷的VSMC中敲低CDK1，我们证明CDK1参与了METTL3调节的VSMC增殖，但这种作用不是由自噬介导的。
我们得出结论，mTOR而非CDK1介导了METTL3对VSMC增殖和自噬的作用。
