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circACTA2 inhibits NLRP3 inflammasome-mediated inflammation via interacting with NF-κB in vascular smooth muscle cells
circACTA2 derived from the smooth muscle α-actin gene plays an important role in the regulation of vascular smooth muscle cell (VSMC) phenotype. The activation of NLRP3 inflammasome is involved in VSMC phenotypic switching. However, the mechanistic relationship between circACTA2 and NLRP3 inflammaso...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10374705/ https://www.ncbi.nlm.nih.gov/pubmed/37498354 http://dx.doi.org/10.1007/s00018-023-04840-6 |
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author | Bai, Yang Zhang, Long Zheng, Bin Zhang, Xinhua Zhang, Hong Zhao, Anning Yu, Jing Yang, Zhan Wen, Jinkun |
author_facet | Bai, Yang Zhang, Long Zheng, Bin Zhang, Xinhua Zhang, Hong Zhao, Anning Yu, Jing Yang, Zhan Wen, Jinkun |
author_sort | Bai, Yang |
collection | PubMed |
description | circACTA2 derived from the smooth muscle α-actin gene plays an important role in the regulation of vascular smooth muscle cell (VSMC) phenotype. The activation of NLRP3 inflammasome is involved in VSMC phenotypic switching. However, the mechanistic relationship between circACTA2 and NLRP3 inflammasome during vascular remodeling remains poorly understood. Here, we showed that circACTA2 was down-regulated in human intimal hyperplasia. circACTA2 overexpression in circACTA2 transgenic mice significantly decreased the neointimal hyperplasia induced by vascular injury, which is concomitant with a decrease in IL-18, IL-1β, TNF-α, and IL-6 levels. Gain- and loss-of-function studies revealed that circACTA2 alleviated VSMC inflammation by suppressing the activation of NLRP3 inflammasome. Mechanistically, circACTA2 inhibited the expression of NF-κB p65 and p50 subunits and interacted with p50, which impedes the formation of the p50/p65 heterodimer and nuclear translocation induced by TNF-α, thus resulting in the suppression of NLRP3 gene transcription and inflammasome activation. Furthermore, circACTA2 overexpression mitigated inflammation via repressing NLRP3 inflammasome-mediated VSMC pyroptosis. Importantly, employing a decoy oligonucleotide to compete with circACTA2 for binding to p50 could attenuate the expression of NLRP3, ASC, and caspase-1. These findings provide a novel insight into the functional roles of circACTA2 in VSMCs, and targeting the circACTA2–NF-κB–NLRP3 axis represents a promising therapeutic strategy for vascular remodeling. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04840-6. |
format | Online Article Text |
id | pubmed-10374705 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-103747052023-07-29 circACTA2 inhibits NLRP3 inflammasome-mediated inflammation via interacting with NF-κB in vascular smooth muscle cells Bai, Yang Zhang, Long Zheng, Bin Zhang, Xinhua Zhang, Hong Zhao, Anning Yu, Jing Yang, Zhan Wen, Jinkun Cell Mol Life Sci Original Article circACTA2 derived from the smooth muscle α-actin gene plays an important role in the regulation of vascular smooth muscle cell (VSMC) phenotype. The activation of NLRP3 inflammasome is involved in VSMC phenotypic switching. However, the mechanistic relationship between circACTA2 and NLRP3 inflammasome during vascular remodeling remains poorly understood. Here, we showed that circACTA2 was down-regulated in human intimal hyperplasia. circACTA2 overexpression in circACTA2 transgenic mice significantly decreased the neointimal hyperplasia induced by vascular injury, which is concomitant with a decrease in IL-18, IL-1β, TNF-α, and IL-6 levels. Gain- and loss-of-function studies revealed that circACTA2 alleviated VSMC inflammation by suppressing the activation of NLRP3 inflammasome. Mechanistically, circACTA2 inhibited the expression of NF-κB p65 and p50 subunits and interacted with p50, which impedes the formation of the p50/p65 heterodimer and nuclear translocation induced by TNF-α, thus resulting in the suppression of NLRP3 gene transcription and inflammasome activation. Furthermore, circACTA2 overexpression mitigated inflammation via repressing NLRP3 inflammasome-mediated VSMC pyroptosis. Importantly, employing a decoy oligonucleotide to compete with circACTA2 for binding to p50 could attenuate the expression of NLRP3, ASC, and caspase-1. These findings provide a novel insight into the functional roles of circACTA2 in VSMCs, and targeting the circACTA2–NF-κB–NLRP3 axis represents a promising therapeutic strategy for vascular remodeling. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-023-04840-6. Springer International Publishing 2023-07-27 2023 /pmc/articles/PMC10374705/ /pubmed/37498354 http://dx.doi.org/10.1007/s00018-023-04840-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Bai, Yang Zhang, Long Zheng, Bin Zhang, Xinhua Zhang, Hong Zhao, Anning Yu, Jing Yang, Zhan Wen, Jinkun circACTA2 inhibits NLRP3 inflammasome-mediated inflammation via interacting with NF-κB in vascular smooth muscle cells |
title | circACTA2 inhibits NLRP3 inflammasome-mediated inflammation via interacting with NF-κB in vascular smooth muscle cells |
title_full | circACTA2 inhibits NLRP3 inflammasome-mediated inflammation via interacting with NF-κB in vascular smooth muscle cells |
title_fullStr | circACTA2 inhibits NLRP3 inflammasome-mediated inflammation via interacting with NF-κB in vascular smooth muscle cells |
title_full_unstemmed | circACTA2 inhibits NLRP3 inflammasome-mediated inflammation via interacting with NF-κB in vascular smooth muscle cells |
title_short | circACTA2 inhibits NLRP3 inflammasome-mediated inflammation via interacting with NF-κB in vascular smooth muscle cells |
title_sort | circacta2 inhibits nlrp3 inflammasome-mediated inflammation via interacting with nf-κb in vascular smooth muscle cells |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10374705/ https://www.ncbi.nlm.nih.gov/pubmed/37498354 http://dx.doi.org/10.1007/s00018-023-04840-6 |
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