The transcription factor PITX1 cooperates with super-enhancers to regulate the expression of DUSP4 and inhibit pyroptosis in pulmonary artery smooth muscle cells
Abstract Background Pulmonary hypertension (PH) is a highly fatal pathophysiological syndrome. The group 1 pulmonary arterial hypertension (PAH) is characterized by acute pulmonary vasoconstriction and chronic vascular remodeling caused by hyperplasia and hypertrophy of pulmonary artery smooth muscl...
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BMC
2025-04-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-025-03222-9 |
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| author | Jingya Zhang Yuyu Song Xinru Wang Xu Wang Songyue Li Xinyue Song Chong Zhao Jing Qi Yunyun Tian Baoshan Zhao Xiaodong Zheng Yan Xing |
| author_facet | Jingya Zhang Yuyu Song Xinru Wang Xu Wang Songyue Li Xinyue Song Chong Zhao Jing Qi Yunyun Tian Baoshan Zhao Xiaodong Zheng Yan Xing |
| author_sort | Jingya Zhang |
| collection | DOAJ |
| description | Abstract Background Pulmonary hypertension (PH) is a highly fatal pathophysiological syndrome. The group 1 pulmonary arterial hypertension (PAH) is characterized by acute pulmonary vasoconstriction and chronic vascular remodeling caused by hyperplasia and hypertrophy of pulmonary artery smooth muscle cells (PASMCs) and chronic inflammation. Pyroptosis is an inflammatory mode of cell death that is regulated by super-enhancers (SEs) and occurs in the setting of tumors and cardiovascular diseases. However, whether SEs are involved in the pathological process of pyroptosis in PAH and the specific mechanism involved remain unclear. Methods Here, we identified the SE target gene DUSP4 via ChIP-seq with an anti-H3K27ac antibody, and bioinformatics predictions revealed that the transcription factor PITX1 can bind to the promoter and SE sequences of DUSP4. The AAV5 vector was used to deliver shRNAs targeting PITX1 and DUSP4 to PASMCs. Results PITX1 overexpression reversed the increase in right ventricular systolic pressure and pulmonary vascular remodeling, restored the PAAT/PAVTI ratio in hypoxic pulmonary hypertension (HPH, Group 3 PH) and SuHx PAH (Group 1 PAH) mice, and suppressed pyroptosis in pulmonary vascular cells. However, knockdown of DUSP4 counteracted the effects of PITX1 overexpression. Similar results were obtained in cultured PASMCs. In addition, treatment with the SE inhibitors JQ1 and iBET decreased the transcription of DUSP4 and increased the expression of hypoxia-induced pyroptosis proteins in PASMCs. Conclusion We confirmed that PITX1 can promote DUSP4 expression by binding to the DUSP4 promoter and SE to reduce pyroptosis in hypoxic PASMCs, providing new insights into the role of SEs and pyroptosis in pulmonary vascular remodeling and a theoretical basis for the treatment of PAH and related diseases. |
| format | Article |
| id | doaj-art-bb8e9b596ee04a1eb225adadf67dbf82 |
| institution | OA Journals |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | Respiratory Research |
| spelling | doaj-art-bb8e9b596ee04a1eb225adadf67dbf822025-08-20T02:28:11ZengBMCRespiratory Research1465-993X2025-04-0126112010.1186/s12931-025-03222-9The transcription factor PITX1 cooperates with super-enhancers to regulate the expression of DUSP4 and inhibit pyroptosis in pulmonary artery smooth muscle cellsJingya Zhang0Yuyu Song1Xinru Wang2Xu Wang3Songyue Li4Xinyue Song5Chong Zhao6Jing Qi7Yunyun Tian8Baoshan Zhao9Xiaodong Zheng10Yan Xing11Department of Pharmacology, Harbin Medical University-DaqingDepartment of Pharmacology, Harbin Medical University-DaqingDepartment of Pharmacology, Harbin Medical University-DaqingDepartment of Pharmacology, Harbin Medical University-DaqingDepartment of Pharmacology, Harbin Medical University-DaqingCollege of Pharmacy, Harbin Medical UniversityDepartment of Literature Retrieval, Harbin Medical UniversityDepartment of Pharmacology, Harbin Medical University-DaqingDepartment of Pathology, Gaozhou People’s HospitalDepartment of Pathology, Harbin Medical University-DaqingDepartment of Medical Genetics, Harbin Medical University-DaqingDepartment of Pharmacology, Harbin Medical University-DaqingAbstract Background Pulmonary hypertension (PH) is a highly fatal pathophysiological syndrome. The group 1 pulmonary arterial hypertension (PAH) is characterized by acute pulmonary vasoconstriction and chronic vascular remodeling caused by hyperplasia and hypertrophy of pulmonary artery smooth muscle cells (PASMCs) and chronic inflammation. Pyroptosis is an inflammatory mode of cell death that is regulated by super-enhancers (SEs) and occurs in the setting of tumors and cardiovascular diseases. However, whether SEs are involved in the pathological process of pyroptosis in PAH and the specific mechanism involved remain unclear. Methods Here, we identified the SE target gene DUSP4 via ChIP-seq with an anti-H3K27ac antibody, and bioinformatics predictions revealed that the transcription factor PITX1 can bind to the promoter and SE sequences of DUSP4. The AAV5 vector was used to deliver shRNAs targeting PITX1 and DUSP4 to PASMCs. Results PITX1 overexpression reversed the increase in right ventricular systolic pressure and pulmonary vascular remodeling, restored the PAAT/PAVTI ratio in hypoxic pulmonary hypertension (HPH, Group 3 PH) and SuHx PAH (Group 1 PAH) mice, and suppressed pyroptosis in pulmonary vascular cells. However, knockdown of DUSP4 counteracted the effects of PITX1 overexpression. Similar results were obtained in cultured PASMCs. In addition, treatment with the SE inhibitors JQ1 and iBET decreased the transcription of DUSP4 and increased the expression of hypoxia-induced pyroptosis proteins in PASMCs. Conclusion We confirmed that PITX1 can promote DUSP4 expression by binding to the DUSP4 promoter and SE to reduce pyroptosis in hypoxic PASMCs, providing new insights into the role of SEs and pyroptosis in pulmonary vascular remodeling and a theoretical basis for the treatment of PAH and related diseases.https://doi.org/10.1186/s12931-025-03222-9Super-enhancerPITX1PyroptosisPulmonary arterial hypertension |
| spellingShingle | Jingya Zhang Yuyu Song Xinru Wang Xu Wang Songyue Li Xinyue Song Chong Zhao Jing Qi Yunyun Tian Baoshan Zhao Xiaodong Zheng Yan Xing The transcription factor PITX1 cooperates with super-enhancers to regulate the expression of DUSP4 and inhibit pyroptosis in pulmonary artery smooth muscle cells Respiratory Research Super-enhancer PITX1 Pyroptosis Pulmonary arterial hypertension |
| title | The transcription factor PITX1 cooperates with super-enhancers to regulate the expression of DUSP4 and inhibit pyroptosis in pulmonary artery smooth muscle cells |
| title_full | The transcription factor PITX1 cooperates with super-enhancers to regulate the expression of DUSP4 and inhibit pyroptosis in pulmonary artery smooth muscle cells |
| title_fullStr | The transcription factor PITX1 cooperates with super-enhancers to regulate the expression of DUSP4 and inhibit pyroptosis in pulmonary artery smooth muscle cells |
| title_full_unstemmed | The transcription factor PITX1 cooperates with super-enhancers to regulate the expression of DUSP4 and inhibit pyroptosis in pulmonary artery smooth muscle cells |
| title_short | The transcription factor PITX1 cooperates with super-enhancers to regulate the expression of DUSP4 and inhibit pyroptosis in pulmonary artery smooth muscle cells |
| title_sort | transcription factor pitx1 cooperates with super enhancers to regulate the expression of dusp4 and inhibit pyroptosis in pulmonary artery smooth muscle cells |
| topic | Super-enhancer PITX1 Pyroptosis Pulmonary arterial hypertension |
| url | https://doi.org/10.1186/s12931-025-03222-9 |
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