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Deficiency of filamin A in smooth muscle cells protects against hypoxia-mediated pulmonary hypertension in mice

Filamin A (FLNA) is a high molecular weight cytoskeleton protein important for cell locomotion. A relationship between FLNA mutations and pulmonary arterial hypertension (PAH) has previously been reported; however, the detailed mechanism remains unclear. The present study aimed to explore the role o...

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Autores principales: Zheng, Yaguo, Ma, Hong, Yan, Yufeng, Ye, Peng, Yu, Wande, Lin, Song, Chen, Shao-Liang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9911089/
https://www.ncbi.nlm.nih.gov/pubmed/36704846
http://dx.doi.org/10.3892/ijmm.2023.5225
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author Zheng, Yaguo
Ma, Hong
Yan, Yufeng
Ye, Peng
Yu, Wande
Lin, Song
Chen, Shao-Liang
author_facet Zheng, Yaguo
Ma, Hong
Yan, Yufeng
Ye, Peng
Yu, Wande
Lin, Song
Chen, Shao-Liang
author_sort Zheng, Yaguo
collection PubMed
description Filamin A (FLNA) is a high molecular weight cytoskeleton protein important for cell locomotion. A relationship between FLNA mutations and pulmonary arterial hypertension (PAH) has previously been reported; however, the detailed mechanism remains unclear. The present study aimed to explore the role of FLNA in vascular smooth muscle cells during the development of PAH. Smooth muscle cell (SMC)-specific FLNA-deficient mice were generated and the mice were then exposed to hypoxia for 28 days to build the mouse model of PAH. Human pulmonary arterial smooth muscle cells (PASMCs) were also cultured and transfected with FLNA small interfering RNA or overexpression plasmids to investigate the effects of FLNA on PASMC proliferation and migration. Notably, compared with control individuals, the expression levels of FLNA were increased in lung tissues from patients with PAH, and it was obviously expressed in the PASMCs of pulmonary arterioles. FLNA deficiency in SMCs attenuated hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. In vitro studies suggested that absence of FLNA impaired PASMC proliferation and migration, and produced lower levels of phosphorylated (p)-PAK-1 and RAC1 activity. However, FLNA overexpression promoted PASMC proliferation and migration, and increased the expression levels of p-PAK-1 and RAC1 activity. The present study highlights the role of FLNA in pulmonary vascular remodeling; therefore, it could serve as a potential target for the treatment of PAH.
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spelling pubmed-99110892023-02-10 Deficiency of filamin A in smooth muscle cells protects against hypoxia-mediated pulmonary hypertension in mice Zheng, Yaguo Ma, Hong Yan, Yufeng Ye, Peng Yu, Wande Lin, Song Chen, Shao-Liang Int J Mol Med Articles Filamin A (FLNA) is a high molecular weight cytoskeleton protein important for cell locomotion. A relationship between FLNA mutations and pulmonary arterial hypertension (PAH) has previously been reported; however, the detailed mechanism remains unclear. The present study aimed to explore the role of FLNA in vascular smooth muscle cells during the development of PAH. Smooth muscle cell (SMC)-specific FLNA-deficient mice were generated and the mice were then exposed to hypoxia for 28 days to build the mouse model of PAH. Human pulmonary arterial smooth muscle cells (PASMCs) were also cultured and transfected with FLNA small interfering RNA or overexpression plasmids to investigate the effects of FLNA on PASMC proliferation and migration. Notably, compared with control individuals, the expression levels of FLNA were increased in lung tissues from patients with PAH, and it was obviously expressed in the PASMCs of pulmonary arterioles. FLNA deficiency in SMCs attenuated hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. In vitro studies suggested that absence of FLNA impaired PASMC proliferation and migration, and produced lower levels of phosphorylated (p)-PAK-1 and RAC1 activity. However, FLNA overexpression promoted PASMC proliferation and migration, and increased the expression levels of p-PAK-1 and RAC1 activity. The present study highlights the role of FLNA in pulmonary vascular remodeling; therefore, it could serve as a potential target for the treatment of PAH. D.A. Spandidos 2023-01-26 /pmc/articles/PMC9911089/ /pubmed/36704846 http://dx.doi.org/10.3892/ijmm.2023.5225 Text en Copyright: © Zheng et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , 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 Articles
Zheng, Yaguo
Ma, Hong
Yan, Yufeng
Ye, Peng
Yu, Wande
Lin, Song
Chen, Shao-Liang
Deficiency of filamin A in smooth muscle cells protects against hypoxia-mediated pulmonary hypertension in mice
title Deficiency of filamin A in smooth muscle cells protects against hypoxia-mediated pulmonary hypertension in mice
title_full Deficiency of filamin A in smooth muscle cells protects against hypoxia-mediated pulmonary hypertension in mice
title_fullStr Deficiency of filamin A in smooth muscle cells protects against hypoxia-mediated pulmonary hypertension in mice
title_full_unstemmed Deficiency of filamin A in smooth muscle cells protects against hypoxia-mediated pulmonary hypertension in mice
title_short Deficiency of filamin A in smooth muscle cells protects against hypoxia-mediated pulmonary hypertension in mice
title_sort deficiency of filamin a in smooth muscle cells protects against hypoxia-mediated pulmonary hypertension in mice
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9911089/
https://www.ncbi.nlm.nih.gov/pubmed/36704846
http://dx.doi.org/10.3892/ijmm.2023.5225
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