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Myotubularin‐Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo‐Like Kinase1

BACKGROUND: 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‐r...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9673629/
https://www.ncbi.nlm.nih.gov/pubmed/36314496
http://dx.doi.org/10.1161/JAHA.122.026174
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author 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
author_facet 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
author_sort Kong, Ling‐Yao
collection PubMed
description BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
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spelling pubmed-96736292022-11-21 Myotubularin‐Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo‐Like Kinase1 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 J Am Heart Assoc Original Research BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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. John Wiley and Sons Inc. 2022-10-31 /pmc/articles/PMC9673629/ /pubmed/36314496 http://dx.doi.org/10.1161/JAHA.122.026174 Text en © 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Research
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
Myotubularin‐Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo‐Like Kinase1
title Myotubularin‐Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo‐Like Kinase1
title_full Myotubularin‐Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo‐Like Kinase1
title_fullStr Myotubularin‐Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo‐Like Kinase1
title_full_unstemmed Myotubularin‐Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo‐Like Kinase1
title_short Myotubularin‐Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo‐Like Kinase1
title_sort myotubularin‐related protein14 prevents neointima formation and vascular smooth muscle cell proliferation by inhibiting polo‐like kinase1
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9673629/
https://www.ncbi.nlm.nih.gov/pubmed/36314496
http://dx.doi.org/10.1161/JAHA.122.026174
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