Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages
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
Affiliations
Li Hu
Department of Forensic Medicine, Nanjing Medical University, Nanjing, China; Gusu School, Nanjing Medical University, Suzhou, China
Yanfang Yu
Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
Yueyao Shen
Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
Huijie Huang
Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
Donghai Lin
Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
Kang Wang
Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
Youjia Yu
Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
Kai Li
Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
Yue Cao
Department of Forensic Medicine, Nanjing Medical University, Nanjing, China
Qiang Wang
Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Xiaoxuan Sun
Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Zhibing Qiu
Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
Dong Wei
Wuxi Lung Transplantation Center, Wuxi People's Hospital Affiliated with Nanjing Medical University, Wuxi, China
Bin Shen
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
Jingyu Chen
Wuxi Lung Transplantation Center, Wuxi People's Hospital Affiliated with Nanjing Medical University, Wuxi, China
David Fulton
Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA, USA
Yong Ji
Key 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, China
Jie Wang
Department of Forensic Medicine, Nanjing Medical University, Nanjing, China; Corresponding author.
Feng Chen
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.
