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Naked cuticle homolog 1 prevents mouse pulmonary arterial hypertension via inhibition of Wnt/β-catenin and oxidative stress
Pulmonary arterial hypertension (PAH) is a poorly prognostic cardiopulmonary disease characterized by abnormal contraction and remodeling of pulmonary artery (PA). Excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) are considered as the major etiology of PA remo...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637826/ https://www.ncbi.nlm.nih.gov/pubmed/37857014 http://dx.doi.org/10.18632/aging.205105 |
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author | Wei, Shanwu Lin, Lu Jiang, Wen Chen, Jie Gong, Gu Sui, Daming |
author_facet | Wei, Shanwu Lin, Lu Jiang, Wen Chen, Jie Gong, Gu Sui, Daming |
author_sort | Wei, Shanwu |
collection | PubMed |
description | Pulmonary arterial hypertension (PAH) is a poorly prognostic cardiopulmonary disease characterized by abnormal contraction and remodeling of pulmonary artery (PA). Excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) are considered as the major etiology of PA remodeling. As a negative regulator of Wnt/β-catenin pathway, naked cuticle homolog 1 (NKD1) is originally involved in the tumor growth and metastasis via affecting the proliferation and migration of different types of cancer cells. However, the effect of NKD1 on PAH development has not been investigated. In the current study, downregulated NKD1 was identified in hypoxia-challenged PASMCs. NKD1 overexpression by adenovirus carrying vector encoding Nkd1 (Ad-Nkd1) repressed hypoxia-induced proliferation and migration of PASMCs. Mechanistically, upregulating NKD1 inhibited excessive reactive oxygen species (ROS) generation and β-catenin expression in PASMCs after hypoxia stimulus. Both inducing ROS and recovering β-catenin expression abolished NKD1-mediated suppression of proliferation and migration in PASMCs. In vivo, we also observed decreased expression of NKD1 in dissected PAs of monocrotaline (MCT)-induced PAH model. Upregulating NKD1 by Ad-Nkd1 transfection attenuated the increase in right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), pulmonary vascular wall thickening, and vascular β-catenin expression after MCT treatment. After recovering β-catenin expression by SKL2001, the vascular protection of external expression of NKD1 was also abolished. Taken together, our data suggest that NKD1 inhibits the proliferation, migration of PASMC, and PAH via inhibition of β-catenin and oxidative stress. Thus, targeting NKD1 may provide novel insights into the prevention and treatment of PAH. |
format | Online Article Text |
id | pubmed-10637826 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Impact Journals |
record_format | MEDLINE/PubMed |
spelling | pubmed-106378262023-11-15 Naked cuticle homolog 1 prevents mouse pulmonary arterial hypertension via inhibition of Wnt/β-catenin and oxidative stress Wei, Shanwu Lin, Lu Jiang, Wen Chen, Jie Gong, Gu Sui, Daming Aging (Albany NY) Research Paper Pulmonary arterial hypertension (PAH) is a poorly prognostic cardiopulmonary disease characterized by abnormal contraction and remodeling of pulmonary artery (PA). Excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) are considered as the major etiology of PA remodeling. As a negative regulator of Wnt/β-catenin pathway, naked cuticle homolog 1 (NKD1) is originally involved in the tumor growth and metastasis via affecting the proliferation and migration of different types of cancer cells. However, the effect of NKD1 on PAH development has not been investigated. In the current study, downregulated NKD1 was identified in hypoxia-challenged PASMCs. NKD1 overexpression by adenovirus carrying vector encoding Nkd1 (Ad-Nkd1) repressed hypoxia-induced proliferation and migration of PASMCs. Mechanistically, upregulating NKD1 inhibited excessive reactive oxygen species (ROS) generation and β-catenin expression in PASMCs after hypoxia stimulus. Both inducing ROS and recovering β-catenin expression abolished NKD1-mediated suppression of proliferation and migration in PASMCs. In vivo, we also observed decreased expression of NKD1 in dissected PAs of monocrotaline (MCT)-induced PAH model. Upregulating NKD1 by Ad-Nkd1 transfection attenuated the increase in right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), pulmonary vascular wall thickening, and vascular β-catenin expression after MCT treatment. After recovering β-catenin expression by SKL2001, the vascular protection of external expression of NKD1 was also abolished. Taken together, our data suggest that NKD1 inhibits the proliferation, migration of PASMC, and PAH via inhibition of β-catenin and oxidative stress. Thus, targeting NKD1 may provide novel insights into the prevention and treatment of PAH. Impact Journals 2023-10-18 /pmc/articles/PMC10637826/ /pubmed/37857014 http://dx.doi.org/10.18632/aging.205105 Text en Copyright: © 2023 Wei et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Wei, Shanwu Lin, Lu Jiang, Wen Chen, Jie Gong, Gu Sui, Daming Naked cuticle homolog 1 prevents mouse pulmonary arterial hypertension via inhibition of Wnt/β-catenin and oxidative stress |
title | Naked cuticle homolog 1 prevents mouse pulmonary arterial hypertension via inhibition of Wnt/β-catenin and oxidative stress |
title_full | Naked cuticle homolog 1 prevents mouse pulmonary arterial hypertension via inhibition of Wnt/β-catenin and oxidative stress |
title_fullStr | Naked cuticle homolog 1 prevents mouse pulmonary arterial hypertension via inhibition of Wnt/β-catenin and oxidative stress |
title_full_unstemmed | Naked cuticle homolog 1 prevents mouse pulmonary arterial hypertension via inhibition of Wnt/β-catenin and oxidative stress |
title_short | Naked cuticle homolog 1 prevents mouse pulmonary arterial hypertension via inhibition of Wnt/β-catenin and oxidative stress |
title_sort | naked cuticle homolog 1 prevents mouse pulmonary arterial hypertension via inhibition of wnt/β-catenin and oxidative stress |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637826/ https://www.ncbi.nlm.nih.gov/pubmed/37857014 http://dx.doi.org/10.18632/aging.205105 |
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