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HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo

BACKGROUND: HMGB1 and ER stress have been considered to participate in the progression of pulmonary artery hypertension (PAH). However, the molecular mechanism underlying HMGB1 and ER stress in PAH remains unclear. This study aims to explore whether HMGB1 induces pulmonary artery smooth muscle cells...

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Autores principales: Zhang, Qianqian, Chen, Yuqian, Wang, Qingting, Wang, Yan, Feng, Wei, Chai, Limin, Liu, Jin, Li, Danyang, Chen, Huan, Qiu, Yuanjie, Shen, Nirui, Shi, Xiangyu, Xie, Xinming, Li, Manxiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10236651/
https://www.ncbi.nlm.nih.gov/pubmed/37268944
http://dx.doi.org/10.1186/s12931-023-02454-x
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author Zhang, Qianqian
Chen, Yuqian
Wang, Qingting
Wang, Yan
Feng, Wei
Chai, Limin
Liu, Jin
Li, Danyang
Chen, Huan
Qiu, Yuanjie
Shen, Nirui
Shi, Xiangyu
Xie, Xinming
Li, Manxiang
author_facet Zhang, Qianqian
Chen, Yuqian
Wang, Qingting
Wang, Yan
Feng, Wei
Chai, Limin
Liu, Jin
Li, Danyang
Chen, Huan
Qiu, Yuanjie
Shen, Nirui
Shi, Xiangyu
Xie, Xinming
Li, Manxiang
author_sort Zhang, Qianqian
collection PubMed
description BACKGROUND: HMGB1 and ER stress have been considered to participate in the progression of pulmonary artery hypertension (PAH). However, the molecular mechanism underlying HMGB1 and ER stress in PAH remains unclear. This study aims to explore whether HMGB1 induces pulmonary artery smooth muscle cells (PASMCs) functions and pulmonary artery remodeling through ER stress activation. METHODS: Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. Cell proliferation and migration were determined by CCK-8, EdU and transwell assay. Western blotting was conducted to detect the protein levels of protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor-4 (ATF4), seven in absentia homolog 2 (SIAH2) and homeodomain interacting protein kinase 2 (HIPK2). Hemodynamic measurements, immunohistochemistry staining, hematoxylin and eosin staining were used to evaluate the development of PAH. The ultrastructure of ER was observed by transmission electron microscopy. RESULTS: In primary cultured PASMCs, HMGB1 reduced HIPK2 expression through upregulation of ER stress-related proteins (PERK and ATF4) and subsequently increased SIAH2 expression, which ultimately led to PASMC proliferation and migration. In MCT-induced PAH rats, interfering with HMGB1 by glycyrrhizin, suppression of ER stress by 4-phenylbutyric acid or targeting SIAH2 by vitamin K3 attenuated the development of PAH. Additionally, tetramethylpyrazine (TMP), as a component of traditional Chinese herbal medicine, reversed hemodynamic deterioration and vascular remodeling by targeting PERK/ATF4/SIAH2/HIPK2 axis. CONCLUSIONS: The present study provides a novel insight to understand the pathogenesis of PAH and suggests that targeting HMGB1/PERK/ATF4/SIAH2/HIPK2 cascade might have potential therapeutic value for the prevention and treatment of PAH. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-023-02454-x.
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spelling pubmed-102366512023-06-03 HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo Zhang, Qianqian Chen, Yuqian Wang, Qingting Wang, Yan Feng, Wei Chai, Limin Liu, Jin Li, Danyang Chen, Huan Qiu, Yuanjie Shen, Nirui Shi, Xiangyu Xie, Xinming Li, Manxiang Respir Res Research BACKGROUND: HMGB1 and ER stress have been considered to participate in the progression of pulmonary artery hypertension (PAH). However, the molecular mechanism underlying HMGB1 and ER stress in PAH remains unclear. This study aims to explore whether HMGB1 induces pulmonary artery smooth muscle cells (PASMCs) functions and pulmonary artery remodeling through ER stress activation. METHODS: Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. Cell proliferation and migration were determined by CCK-8, EdU and transwell assay. Western blotting was conducted to detect the protein levels of protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor-4 (ATF4), seven in absentia homolog 2 (SIAH2) and homeodomain interacting protein kinase 2 (HIPK2). Hemodynamic measurements, immunohistochemistry staining, hematoxylin and eosin staining were used to evaluate the development of PAH. The ultrastructure of ER was observed by transmission electron microscopy. RESULTS: In primary cultured PASMCs, HMGB1 reduced HIPK2 expression through upregulation of ER stress-related proteins (PERK and ATF4) and subsequently increased SIAH2 expression, which ultimately led to PASMC proliferation and migration. In MCT-induced PAH rats, interfering with HMGB1 by glycyrrhizin, suppression of ER stress by 4-phenylbutyric acid or targeting SIAH2 by vitamin K3 attenuated the development of PAH. Additionally, tetramethylpyrazine (TMP), as a component of traditional Chinese herbal medicine, reversed hemodynamic deterioration and vascular remodeling by targeting PERK/ATF4/SIAH2/HIPK2 axis. CONCLUSIONS: The present study provides a novel insight to understand the pathogenesis of PAH and suggests that targeting HMGB1/PERK/ATF4/SIAH2/HIPK2 cascade might have potential therapeutic value for the prevention and treatment of PAH. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-023-02454-x. BioMed Central 2023-06-02 2023 /pmc/articles/PMC10236651/ /pubmed/37268944 http://dx.doi.org/10.1186/s12931-023-02454-x 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Zhang, Qianqian
Chen, Yuqian
Wang, Qingting
Wang, Yan
Feng, Wei
Chai, Limin
Liu, Jin
Li, Danyang
Chen, Huan
Qiu, Yuanjie
Shen, Nirui
Shi, Xiangyu
Xie, Xinming
Li, Manxiang
HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo
title HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo
title_full HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo
title_fullStr HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo
title_full_unstemmed HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo
title_short HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo
title_sort hmgb1-induced activation of er stress contributes to pulmonary artery hypertension in vitro and in vivo
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10236651/
https://www.ncbi.nlm.nih.gov/pubmed/37268944
http://dx.doi.org/10.1186/s12931-023-02454-x
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