Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages
Pulmonary hypertension (PH) is a devastating disease characterized by irreversible pulmonary vascular remodeling (PVR) that causes right ventricular failure and death. The early alternative activation of macrophages is a critical event in the development of PVR and PH, but the underlying mechanisms...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723000393 |
| _version_ | 1811154725746245632 |
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| author | Li Hu Yanfang Yu Yueyao Shen Huijie Huang Donghai Lin Kang Wang Youjia Yu Kai Li Yue Cao Qiang Wang Xiaoxuan Sun Zhibing Qiu Dong Wei Bin Shen Jingyu Chen David Fulton Yong Ji Jie Wang Feng Chen |
| author_facet | Li Hu Yanfang Yu Yueyao Shen Huijie Huang Donghai Lin Kang Wang Youjia Yu Kai Li Yue Cao Qiang Wang Xiaoxuan Sun Zhibing Qiu Dong Wei Bin Shen Jingyu Chen David Fulton Yong Ji Jie Wang Feng Chen |
| author_sort | Li Hu |
| collection | DOAJ |
| description | Pulmonary hypertension (PH) is a devastating disease characterized by irreversible pulmonary vascular remodeling (PVR) that causes right ventricular failure and death. The early alternative activation of macrophages is a critical event in the development of PVR and PH, but the underlying mechanisms remain elusive. Previously we have shown that N6-methyladenosine (m6A) modifications of RNA contribute to phenotypic switching of pulmonary artery smooth muscle cells and PH. In the current study, we identify Ythdf2, an m6A reader, as an important regulator of pulmonary inflammation and redox regulation in PH. In a mouse model of PH, the protein expression of Ythdf2 was increased in alveolar macrophages (AMs) during the early stages of hypoxia. Mice with a myeloid specific knockout of Ythdf2 (Ythdf2Lyz2 Cre) were protected from PH with attenuated right ventricular hypertrophy and PVR compared to control mice and this was accompanied by decreased macrophage polarization and oxidative stress. In the absence of Ythdf2, heme oxygenase 1 (Hmox1) mRNA and protein expression were significantly elevated in hypoxic AMs. Mechanistically, Ythdf2 promoted the degradation of Hmox1 mRNA in a m6A dependent manner. Furthermore, an inhibitor of Hmox1 promoted macrophage alternative activation, and reversed the protection from PH seen in Ythdf2Lyz2 Cre mice under hypoxic exposure. Together, our data reveal a novel mechanism linking m6A RNA modification with changes in macrophage phenotype, inflammation and oxidative stress in PH, and identify Hmox1 as a downstream target of Ythdf2, suggesting that Ythdf2 may be a therapeutic target in PH. |
| first_indexed | 2024-04-10T04:21:53Z |
| format | Article |
| id | doaj.art-91d134e9a9a54851932ce108a81529bf |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-10T04:21:53Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-91d134e9a9a54851932ce108a81529bf2023-03-11T04:19:38ZengElsevierRedox Biology2213-23172023-05-0161102638Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophagesLi Hu0Yanfang Yu1Yueyao Shen2Huijie Huang3Donghai Lin4Kang Wang5Youjia Yu6Kai Li7Yue Cao8Qiang Wang9Xiaoxuan Sun10Zhibing Qiu11Dong Wei12Bin Shen13Jingyu Chen14David Fulton15Yong Ji16Jie Wang17Feng Chen18Department of Forensic Medicine, Nanjing Medical University, Nanjing, China; Gusu School, Nanjing Medical University, Suzhou, ChinaDepartment of Forensic Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Forensic Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Forensic Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Forensic Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Forensic Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Forensic Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Forensic Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Forensic Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, ChinaWuxi Lung Transplantation Center, Wuxi People's Hospital Affiliated with Nanjing Medical University, Wuxi, ChinaState Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, ChinaWuxi Lung Transplantation Center, Wuxi People's Hospital Affiliated with Nanjing Medical University, Wuxi, ChinaVascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USAKey Laboratory of Cardiovascular and Cerebrovascular Medicine, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, ChinaDepartment of Forensic Medicine, Nanjing Medical University, Nanjing, China; Corresponding author.Department of Forensic Medicine, Nanjing Medical University, Nanjing, China; Gusu School, Nanjing Medical University, Suzhou, China; Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China; Corresponding author. Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, Jiangsu 210029, China.Pulmonary hypertension (PH) is a devastating disease characterized by irreversible pulmonary vascular remodeling (PVR) that causes right ventricular failure and death. The early alternative activation of macrophages is a critical event in the development of PVR and PH, but the underlying mechanisms remain elusive. Previously we have shown that N6-methyladenosine (m6A) modifications of RNA contribute to phenotypic switching of pulmonary artery smooth muscle cells and PH. In the current study, we identify Ythdf2, an m6A reader, as an important regulator of pulmonary inflammation and redox regulation in PH. In a mouse model of PH, the protein expression of Ythdf2 was increased in alveolar macrophages (AMs) during the early stages of hypoxia. Mice with a myeloid specific knockout of Ythdf2 (Ythdf2Lyz2 Cre) were protected from PH with attenuated right ventricular hypertrophy and PVR compared to control mice and this was accompanied by decreased macrophage polarization and oxidative stress. In the absence of Ythdf2, heme oxygenase 1 (Hmox1) mRNA and protein expression were significantly elevated in hypoxic AMs. Mechanistically, Ythdf2 promoted the degradation of Hmox1 mRNA in a m6A dependent manner. Furthermore, an inhibitor of Hmox1 promoted macrophage alternative activation, and reversed the protection from PH seen in Ythdf2Lyz2 Cre mice under hypoxic exposure. Together, our data reveal a novel mechanism linking m6A RNA modification with changes in macrophage phenotype, inflammation and oxidative stress in PH, and identify Hmox1 as a downstream target of Ythdf2, suggesting that Ythdf2 may be a therapeutic target in PH.http://www.sciencedirect.com/science/article/pii/S2213231723000393Alveolar macrophagesOxidant stressInflammationYthdf2Heme oxygenase 1Pulmonary hypertension |
| spellingShingle | Li Hu Yanfang Yu Yueyao Shen Huijie Huang Donghai Lin Kang Wang Youjia Yu Kai Li Yue Cao Qiang Wang Xiaoxuan Sun Zhibing Qiu Dong Wei Bin Shen Jingyu Chen David Fulton Yong Ji Jie Wang Feng Chen Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages Redox Biology Alveolar macrophages Oxidant stress Inflammation Ythdf2 Heme oxygenase 1 Pulmonary hypertension |
| title | Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages |
| title_full | Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages |
| title_fullStr | Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages |
| title_full_unstemmed | Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages |
| title_short | Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages |
| title_sort | ythdf2 promotes pulmonary hypertension by suppressing hmox1 dependent anti inflammatory and antioxidant function in alveolar macrophages |
| topic | Alveolar macrophages Oxidant stress Inflammation Ythdf2 Heme oxygenase 1 Pulmonary hypertension |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723000393 |
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