Loss of Type 2 Bone Morphogenetic Protein Receptor Activates NOD‐Like Receptor Family Protein 3/Gasdermin E‐Mediated Pyroptosis in Pulmonary Arterial Hypertension
BACKGROUND Pulmonary arterial hypertension (PAH) is an incurable disease initiated by endothelial dysfunction, secondary to vascular inflammation and occlusive pulmonary arterial vascular remodeling, resulting in elevated pulmonary arterial pressure and right heart failure. Previous research has rep...
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Wiley
2025-02-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.034726 |
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| author | Xiao‐ting Tian Zhou‐yang‐fan Peng Yu‐si Wu Yuan‐yuan Cao Xue‐chun Li Ying Li Si‐Yuan Tang Alex F. Chen Xiao‐hui Li |
| author_facet | Xiao‐ting Tian Zhou‐yang‐fan Peng Yu‐si Wu Yuan‐yuan Cao Xue‐chun Li Ying Li Si‐Yuan Tang Alex F. Chen Xiao‐hui Li |
| author_sort | Xiao‐ting Tian |
| collection | DOAJ |
| description | BACKGROUND Pulmonary arterial hypertension (PAH) is an incurable disease initiated by endothelial dysfunction, secondary to vascular inflammation and occlusive pulmonary arterial vascular remodeling, resulting in elevated pulmonary arterial pressure and right heart failure. Previous research has reported that dysfunction of type 2 bone morphogenetic protein receptor (BMPR2) signaling pathway in endothelium is inclined to prompt inflammation in PAH models, but the underlying mechanism of BMPR2 deficiency‐mediated inflammation needs further investigation. This study was designed to investigate whether BMPR2 deficiency contributes to pulmonary arterial hypertension via the NLRP3 (NOD‐like receptor family protein 3)/GSDME (gasdermin E)‐mediated pyroptosis pathway. METHODS AND RESULTS NLRP3 knockout or short hairpin RNA interference of GSDME was performed in PAH animal models to investigate its effect on PAH progression. In addition, the effects of BMPR2 deficiency and restoration of BMPR2 by BMP9 (bone morphogenetic protein 9) or FK506 on pyroptosis were explored both in animal and cell models. Knockout of NLRP3 or short hairpin RNA interference of GSDME in animal models can alleviate the development of pyroptosis, accompanied with improved endothelial integrity, vascular remodeling, and right ventricular systolic pressure. Blocking BMPR2 is sufficient to induce NLRP3 upregulation and release of inflammatory factor IL‐1β (interleukin‐1β) in pulmonary arterial endothelial cells. Moreover, BMPR2 deficiency can induce GSDME‐mediated pyroptosis through NLRP3 activation in 2 animal models, whereas activation of BMPR2 signaling by FK506 or BMP9 can reverse these phenotypes. CONCLUSIONS These findings provide evidence that loss of BMPR2 signaling promotes endothelial cell pyroptosis by enhancing NLRP3/GSDME signaling in PAH. Our findings may provide new insights to explore the inflammatory mechanism of PAH treatment. |
| format | Article |
| id | doaj-art-50686ce0c8cb480caf5bfd6ca98ff9ce |
| institution | Kabale University |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-50686ce0c8cb480caf5bfd6ca98ff9ce2025-02-04T11:00:01ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-02-0114310.1161/JAHA.124.034726Loss of Type 2 Bone Morphogenetic Protein Receptor Activates NOD‐Like Receptor Family Protein 3/Gasdermin E‐Mediated Pyroptosis in Pulmonary Arterial HypertensionXiao‐ting Tian0Zhou‐yang‐fan Peng1Yu‐si Wu2Yuan‐yuan Cao3Xue‐chun Li4Ying Li5Si‐Yuan Tang6Alex F. Chen7Xiao‐hui Li8The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital Central South University Changsha Hunan ChinaThe Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital Central South University Changsha Hunan ChinaThe Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital Central South University Changsha Hunan ChinaDepartment of Pharmacology, Xiangya School of Pharmaceutical Science Central South University Changsha ChinaInstitute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Shanghai Jiao Tong University School of Medicine Shanghai ChinaHunan Key Laboratory for Bioanalysis of Complex Matrix Samples Changsha ChinaXiangya Nursing School Central South University Changsha ChinaThe Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital Central South University Changsha Hunan ChinaThe Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital Central South University Changsha Hunan ChinaBACKGROUND Pulmonary arterial hypertension (PAH) is an incurable disease initiated by endothelial dysfunction, secondary to vascular inflammation and occlusive pulmonary arterial vascular remodeling, resulting in elevated pulmonary arterial pressure and right heart failure. Previous research has reported that dysfunction of type 2 bone morphogenetic protein receptor (BMPR2) signaling pathway in endothelium is inclined to prompt inflammation in PAH models, but the underlying mechanism of BMPR2 deficiency‐mediated inflammation needs further investigation. This study was designed to investigate whether BMPR2 deficiency contributes to pulmonary arterial hypertension via the NLRP3 (NOD‐like receptor family protein 3)/GSDME (gasdermin E)‐mediated pyroptosis pathway. METHODS AND RESULTS NLRP3 knockout or short hairpin RNA interference of GSDME was performed in PAH animal models to investigate its effect on PAH progression. In addition, the effects of BMPR2 deficiency and restoration of BMPR2 by BMP9 (bone morphogenetic protein 9) or FK506 on pyroptosis were explored both in animal and cell models. Knockout of NLRP3 or short hairpin RNA interference of GSDME in animal models can alleviate the development of pyroptosis, accompanied with improved endothelial integrity, vascular remodeling, and right ventricular systolic pressure. Blocking BMPR2 is sufficient to induce NLRP3 upregulation and release of inflammatory factor IL‐1β (interleukin‐1β) in pulmonary arterial endothelial cells. Moreover, BMPR2 deficiency can induce GSDME‐mediated pyroptosis through NLRP3 activation in 2 animal models, whereas activation of BMPR2 signaling by FK506 or BMP9 can reverse these phenotypes. CONCLUSIONS These findings provide evidence that loss of BMPR2 signaling promotes endothelial cell pyroptosis by enhancing NLRP3/GSDME signaling in PAH. Our findings may provide new insights to explore the inflammatory mechanism of PAH treatment.https://www.ahajournals.org/doi/10.1161/JAHA.124.034726BMPR2GSDMENLRP3pulmonary arterial hypertensionpyroptosis |
| spellingShingle | Xiao‐ting Tian Zhou‐yang‐fan Peng Yu‐si Wu Yuan‐yuan Cao Xue‐chun Li Ying Li Si‐Yuan Tang Alex F. Chen Xiao‐hui Li Loss of Type 2 Bone Morphogenetic Protein Receptor Activates NOD‐Like Receptor Family Protein 3/Gasdermin E‐Mediated Pyroptosis in Pulmonary Arterial Hypertension Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease BMPR2 GSDME NLRP3 pulmonary arterial hypertension pyroptosis |
| title | Loss of Type 2 Bone Morphogenetic Protein Receptor Activates NOD‐Like Receptor Family Protein 3/Gasdermin E‐Mediated Pyroptosis in Pulmonary Arterial Hypertension |
| title_full | Loss of Type 2 Bone Morphogenetic Protein Receptor Activates NOD‐Like Receptor Family Protein 3/Gasdermin E‐Mediated Pyroptosis in Pulmonary Arterial Hypertension |
| title_fullStr | Loss of Type 2 Bone Morphogenetic Protein Receptor Activates NOD‐Like Receptor Family Protein 3/Gasdermin E‐Mediated Pyroptosis in Pulmonary Arterial Hypertension |
| title_full_unstemmed | Loss of Type 2 Bone Morphogenetic Protein Receptor Activates NOD‐Like Receptor Family Protein 3/Gasdermin E‐Mediated Pyroptosis in Pulmonary Arterial Hypertension |
| title_short | Loss of Type 2 Bone Morphogenetic Protein Receptor Activates NOD‐Like Receptor Family Protein 3/Gasdermin E‐Mediated Pyroptosis in Pulmonary Arterial Hypertension |
| title_sort | loss of type 2 bone morphogenetic protein receptor activates nod like receptor family protein 3 gasdermin e mediated pyroptosis in pulmonary arterial hypertension |
| topic | BMPR2 GSDME NLRP3 pulmonary arterial hypertension pyroptosis |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.034726 |
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