STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines
Abstract Background Obstructive sleep apnea (OSA) is frequently associated with increased incidence and mortality of pulmonary hypertension (PH). The immune response contributes to pulmonary artery remodeling and OSA-related diseases. The immunologic factors linked to OSA-induced PH are not well und...
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BMC
2025-01-01
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| Series: | Respiratory Research |
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| Online Access: | https://doi.org/10.1186/s12931-024-03062-z |
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| author | Pan Jiang Huai Huang Zilong Liu Guiling Xiang Xiaodan Wu Shengyu Hao Shanqun Li |
| author_facet | Pan Jiang Huai Huang Zilong Liu Guiling Xiang Xiaodan Wu Shengyu Hao Shanqun Li |
| author_sort | Pan Jiang |
| collection | DOAJ |
| description | Abstract Background Obstructive sleep apnea (OSA) is frequently associated with increased incidence and mortality of pulmonary hypertension (PH). The immune response contributes to pulmonary artery remodeling and OSA-related diseases. The immunologic factors linked to OSA-induced PH are not well understood. STAT6 is crucial in the signaling pathway that modulates immune response. However, the status of phosphorylated STAT6 (p-STAT6) in an OSA-induced PH mouse model remains largely unexplored. Methods Chronic intermittent hypoxia (CIH) plays a crucial role in the progression of OSA. This study utilized a in vivo CIH model to examine the role of STAT6 in CIH-induced PH. Results CIH mice exhibited pulmonary artery remodeling and pulmonary hypertension, indicated by increased right ventricular systolic pressure (RVSP), higher right ventricular to left ventricular plus septum (RV/LV + S) ratios, and significant morphological alterations compared to normoxic (Nor) mice. Increased p-STAT6 in the lungs and elevated p-STAT6 + IL-4 + producing T cells in CIH mice. STAT6 deficiency (STAT6-/-) improved PH and PA remodeling in CIH-induced PH mouse models.STAT6 deficiency impaired the T helper 2 (Th2) immune response, affecting IL-4 and IL-13 secretion. IL-4, rather than IL-13, activated STAT6 in human pulmonary artery smooth muscle cells (hPASMCs). STAT6 knockdown decreased the proliferation in IL-4 treated hPASMCs. Conclusion These findings exhibit the critical role of STAT6 in the pathogenesis of CIH induced PH by regulating Th2 immune response.STAT6 could be a significant therapeutic target for OSA-related PH. |
| format | Article |
| id | doaj-art-9df0128f9dda4297b8f0483779b71e44 |
| institution | Kabale University |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Respiratory Research |
| spelling | doaj-art-9df0128f9dda4297b8f0483779b71e442025-01-19T12:36:29ZengBMCRespiratory Research1465-993X2025-01-0126111410.1186/s12931-024-03062-zSTAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokinesPan Jiang0Huai Huang1Zilong Liu2Guiling Xiang3Xiaodan Wu4Shengyu Hao5Shanqun Li6Department of Pulmonary Medicine, Zhongshan Hospital, Fudan UniversityDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan UniversityDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan UniversityDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan UniversityDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan UniversityDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan UniversityDepartment of Pulmonary Medicine, Zhongshan Hospital, Fudan UniversityAbstract Background Obstructive sleep apnea (OSA) is frequently associated with increased incidence and mortality of pulmonary hypertension (PH). The immune response contributes to pulmonary artery remodeling and OSA-related diseases. The immunologic factors linked to OSA-induced PH are not well understood. STAT6 is crucial in the signaling pathway that modulates immune response. However, the status of phosphorylated STAT6 (p-STAT6) in an OSA-induced PH mouse model remains largely unexplored. Methods Chronic intermittent hypoxia (CIH) plays a crucial role in the progression of OSA. This study utilized a in vivo CIH model to examine the role of STAT6 in CIH-induced PH. Results CIH mice exhibited pulmonary artery remodeling and pulmonary hypertension, indicated by increased right ventricular systolic pressure (RVSP), higher right ventricular to left ventricular plus septum (RV/LV + S) ratios, and significant morphological alterations compared to normoxic (Nor) mice. Increased p-STAT6 in the lungs and elevated p-STAT6 + IL-4 + producing T cells in CIH mice. STAT6 deficiency (STAT6-/-) improved PH and PA remodeling in CIH-induced PH mouse models.STAT6 deficiency impaired the T helper 2 (Th2) immune response, affecting IL-4 and IL-13 secretion. IL-4, rather than IL-13, activated STAT6 in human pulmonary artery smooth muscle cells (hPASMCs). STAT6 knockdown decreased the proliferation in IL-4 treated hPASMCs. Conclusion These findings exhibit the critical role of STAT6 in the pathogenesis of CIH induced PH by regulating Th2 immune response.STAT6 could be a significant therapeutic target for OSA-related PH.https://doi.org/10.1186/s12931-024-03062-zChronic intermittent hypoxiaPulmonary hypertensionSTAT6Th2 immune response |
| spellingShingle | Pan Jiang Huai Huang Zilong Liu Guiling Xiang Xiaodan Wu Shengyu Hao Shanqun Li STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines Respiratory Research Chronic intermittent hypoxia Pulmonary hypertension STAT6 Th2 immune response |
| title | STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines |
| title_full | STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines |
| title_fullStr | STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines |
| title_full_unstemmed | STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines |
| title_short | STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines |
| title_sort | stat6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing th2 inducing cytokines |
| topic | Chronic intermittent hypoxia Pulmonary hypertension STAT6 Th2 immune response |
| url | https://doi.org/10.1186/s12931-024-03062-z |
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