Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages.
Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages.
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YTHDF2通过抑制肺泡巨噬细胞中HMOX1依赖性抗炎和抗氧化功能来促进肺动脉高压。
DOI：
10.1016/j.redox.2023.102638
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发表时间：
2023-05
期刊：
影响因子：
11.4
通讯作者：
Chen, Feng
中科院分区：
文献类型：
--
作者：
Hu, Li;Yu, Yanfang;Shen, Yueyao;Huang, Huijie;Lin, Donghai;Wang, Kang;Yu, Youjia;Li, Kai;Cao, Yue;Wang, Qiang;Sun, Xiaoxuan;Qiu, Zhibing;Wei, Dong;Shen, Bin;Chen, Jingyu;Fulton, David;Ji, Yong;Wang, Jie;Chen, Feng
肺动脉高压（PH）是一种以不可逆的肺血管重构（PVR）为特征的毁灭性疾病，可导致右心室衰竭和死亡。巨噬细胞的早期交替激活是PVR和PH发展的关键事件，但其潜在机制仍不清楚。以前，我们已经表明，N6-甲基腺苷（m6 A）修饰的RNA有助于肺动脉平滑肌细胞和PH的表型转换。在目前的研究中，我们确定Ythdf 2，m6 A阅读器，作为肺炎症和PH氧化还原调节的重要调节因子。在PH小鼠模型中，缺氧早期肺泡巨噬细胞（AM）中Ythdf 2的蛋白表达增加。与对照组小鼠相比，骨髓特异性敲除Ythdf 2（Ythdf 2Lyz 2 Cre）的小鼠免受PH的影响，右心室肥大和PVR减弱，这伴随着巨噬细胞极化和氧化应激的降低。在缺乏Ythdf 2的情况下，缺氧AM中血红素加氧酶1（Hmox 1）mRNA和蛋白表达显著升高。Ythdf 2以m6 A依赖的方式促进Hmox 1 mRNA的降解。此外，Hmox 1的抑制剂促进巨噬细胞交替激活，并逆转了在缺氧暴露下Ythdf 2Lyz 2 Cre小鼠中观察到的PH保护。总之，我们的数据揭示了一种新的机制连接m6 A RNA修饰与巨噬细胞表型的变化，炎症和氧化应激在PH，并确定Hmox 1作为下游的Ythdf 2的目标，这表明Ythdf 2可能是一个治疗目标在PH。Ythdf 2上调肺泡巨噬细胞在PH的早期阶段。髓样Ythdf 2缺陷减轻SU 5416/缺氧诱导的PH小鼠。在肺泡巨噬细胞中，ythdf 2缺失减弱炎症和氧化应激。Ythdf 2通过降解m6 A修饰的Hmox 1 mRNA促进PH的发病。Ythdf 2/Hmox 1通路可能成为PH诊断和治疗的潜在靶点。
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. Ythdf2 was upregulated in alveolar macrophages at the early stage of PH. Myeloid Ythdf2 deficiency alleviated SU5416/hypoxia induced PH in mice. Ythdf2 absence attenuated inflammation and oxidative stress in alveolar macrophages. Ythdf2 promote PH pathogenesis by degrading m6A modified Hmox1 mRNA. Ythdf2/Hmox1 pathway can be a potential target for PH diagnosis and treatment.
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影响因子：
14.9
作者：
Luo X;Li H;Liang J;Zhao Q;Xie Y;Ren J;Zuo Z
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影响因子：
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DOI：
10.1007/978-3-030-68748-9_17
发表时间：
2021-01-01
期刊：
LUNG INFLAMMATION IN HEALTH AND DISEASE, VOL II
影响因子：
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作者：
Katseff, Adiya;Alhawaj, Raed;Wolin, Michael S.
通讯作者：
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