HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo
Abstract 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 musc...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-06-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-023-02454-x |
| _version_ | 1797811350619029504 |
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| author | Qianqian Zhang Yuqian Chen Qingting Wang Yan Wang Wei Feng Limin Chai Jin Liu Danyang Li Huan Chen Yuanjie Qiu Nirui Shen Xiangyu Shi Xinming Xie Manxiang Li |
| author_facet | Qianqian Zhang Yuqian Chen Qingting Wang Yan Wang Wei Feng Limin Chai Jin Liu Danyang Li Huan Chen Yuanjie Qiu Nirui Shen Xiangyu Shi Xinming Xie Manxiang Li |
| author_sort | Qianqian Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-13T07:21:21Z |
| format | Article |
| id | doaj.art-8e58efba898f40489383f13bc067a990 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-03-13T07:21:21Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-8e58efba898f40489383f13bc067a9902023-06-04T11:36:43ZengBMCRespiratory Research1465-993X2023-06-0124111210.1186/s12931-023-02454-xHMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivoQianqian Zhang0Yuqian Chen1Qingting Wang2Yan Wang3Wei Feng4Limin Chai5Jin Liu6Danyang Li7Huan Chen8Yuanjie Qiu9Nirui Shen10Xiangyu Shi11Xinming Xie12Manxiang Li13Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-Sen UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong UniversityAbstract 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.https://doi.org/10.1186/s12931-023-02454-xPulmonary artery hypertensionHMGB1ER stressTetramethylpyrazine |
| spellingShingle | Qianqian Zhang Yuqian Chen Qingting Wang Yan Wang Wei Feng Limin Chai Jin Liu Danyang Li Huan Chen Yuanjie Qiu Nirui Shen Xiangyu Shi Xinming Xie Manxiang Li HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo Respiratory Research Pulmonary artery hypertension HMGB1 ER stress Tetramethylpyrazine |
| 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 | Pulmonary artery hypertension HMGB1 ER stress Tetramethylpyrazine |
| url | https://doi.org/10.1186/s12931-023-02454-x |
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