Myotubularin-Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo-Like Kinase1.
Myotubularin-Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo-Like Kinase1.
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DOI：
10.1161/jaha.122.026174
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发表时间：
2022-11
影响因子：
5.4
通讯作者：
Zhang, Yan-Zhou
中科院分区：
文献类型：
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作者：
Kong, Ling-Yao;Liang, Cui;Li, Peng-Cheng;Zhang, Yi-Wei;Feng, Sheng-Dong;Zhang, Dian-Hong;Yao, Rui;Yang, Lu-Lu;Hao, Zheng-Yang;Zhang, Hao;Tian, Xiao-Xu;Guo, Chen-Ran;Du, Bin-Bin;Dong, Jian-Zeng;Zhang, Yan-Zhou
再狭窄是制约心血管介入治疗进一步发展的主要瓶颈之一。参与这一进程的新信号分子不断被发现；然而，具体的分子机制尚不清楚。MTMR14（肌管蛋白相关蛋白14）是一种新型磷酸肌醇磷酸酶，具有多种生物学功能，参与多种生物过程。然而，MTMR14在血管生物学中的作用尚不清楚。在此，我们研究了MTMR14在血管损伤后新内膜形成和血管平滑肌细胞（VSMC）增殖中的作用。使用SMC特异性条件MTMR14敲除和转基因小鼠建立血管损伤模型。采用组织病理学方法评估新生内膜的形成，采用基于荧光泛素化的细胞周期指标、transwell和划伤试验评估VSMC的增殖和迁移。损伤后新生内膜形成增加，MTMR14表达增加。MTMR14缺乏加速了新内膜的形成，促进了损伤后VSMC的增殖，而MTMR14过表达显著减弱了这一过程。在机制上，我们证明MTMR14通过与PLK1相互作用抑制PLK1 （polo样激酶1）的激活，从而进一步抑制MEK/ERK/AKT（丝裂原活化蛋白激酶/细胞外信号调节激酶/蛋白激酶B）的激活，从而抑制VSMC从内膜向内膜的增殖，从而防止新内膜的形成。MTMR14通过抑制PLK1阻止新生内膜形成和VSMC增殖。我们的研究结果表明，MTMR14可以作为VSMC增殖的抑制剂，并在MTMR14和PLK1之间建立了调节VSMC增殖的联系。MTMR14可能成为治疗再狭窄的一个新的潜在靶点。
Restenosis is one of the main bottlenecks in restricting the further development of cardiovascular interventional therapy. New signaling molecules involved in the progress have continuously been discovered; however, the specific molecular mechanisms remain unclear. MTMR14 (myotubularin‐related protein 14) is a novel phosphoinositide phosphatase that has a variety of biological functions and is involved in diverse biological processes. However, the role of MTMR14 in vascular biology remains unclear. Herein, we addressed the role of MTMR14 in neointima formation and vascular smooth muscle cell (VSMC) proliferation after vessel injury. Vessel injury models were established using SMC‐specific conditional MTMR14‐knockout and ‐transgenic mice. Neointima formation was assessed by histopathological methods, and VSMC proliferation and migration were assessed using fluorescence ubiquitination‐based cell cycle indicator, transwell, and scratch wound assay. Neointima formation and the expression of MTMR14 was increased after injury. MTMR14 deficiency accelerated neointima formation and promoted VSMC proliferation after injury, whereas MTMR14 overexpression remarkably attenuated this process. Mechanistically, we demonstrated that MTMR14 suppressed the activation of PLK1 (polo‐like kinase 1) by interacting with it, which further leads to the inhibition of the activation of MEK/ERK/AKT (mitogen‐activated protein kinase kinase/extracellular‐signal‐regulated kinase/protein kinase B), thereby inhibiting the proliferation of VSMC from the medial to the intima and thus preventing neointima formation. MTMR14 prevents neointima formation and VSMC proliferation by inhibiting PLK1. Our findings reveal that MTMR14 serves as an inhibitor of VSMC proliferation and establish a link between MTMR14 and PLK1 in regulating VSMC proliferation. MTMR14 may become a novel potential therapeutic target in the treatment of restenosis.