Zhou Pan, Yan Yao, Xu Liu, Yixuan Wang, Xinyue Zhang, Shiqian Zha, Ke Hu
{"title":"抑制 Nr1d1 可通过 Dusp1 介导的 Erk1/2 失活和线粒体裂变衰减缓解间歇性缺氧诱发的肺动脉高压。","authors":"Zhou Pan, Yan Yao, Xu Liu, Yixuan Wang, Xinyue Zhang, Shiqian Zha, Ke Hu","doi":"10.1038/s41420-024-02219-5","DOIUrl":null,"url":null,"abstract":"<p><p>Intermittent hypoxia (IH) precipitates pulmonary vasoconstriction, culminating in the onset of pulmonary hypertension (PH) among individuals afflicted with sleep apnea. While Nuclear receptor subfamily 1 group D member 1 (Nr1d1) is progressively recognized as pivotal regulator of cellular physiology, the role in the pathogenesis of IH-induced PH remains largely uncharted. The expression of Nr1d1 was examined in IH-induced rodent PH and in IH-treated PASMCs. To elucidate the contribution of Nr1d1 to the development of IH-induced PH, we employed siRNA to modulate Nr1d1 expression in vitro and employed serotype 1 adeno-associated virus (AAV1) in vivo. Nr1d1 levels were elevated in IH-induced rodents PH lung tissues and IH-treated PASMCs. Knocking down Nr1d1 by AAV1 effectively inhibited PH progression in chronic IH-induced PH models. Mechanistic investigations identified dual specificity phosphatase 1 (Dusp1), as a direct target that Nr1d1 trans-repressed, mediating Nr1d1's regulatory influence on Erk1/2/Drp1 signaling. Nr1d1 deficiency ameliorates mitochondrial dysfunction and fission by restoring Dusp1 dysregulation and Drp1 phosphorylation. Activation of Erk1/2 with PMA reversed the Dusp1-mediated regulation of Drp1 phosphorylation, indicating the involvement of the Erk1/2 pathway in Drp1 phosphorylation controlled by Dusp1. Meanwhile, intermittent hypoxia induced more severe PH in Dusp1 knockout mice compared with wild-type mice. Our data unveil a novel role for Nr1d1 in IH-induced PH pathogenesis and an undisclosed Nr1d1-Dusp1 axis in PASMCs mitochondrial fission regulation.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":null,"pages":null},"PeriodicalIF":6.1000,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522549/pdf/","citationCount":"0","resultStr":"{\"title\":\"Nr1d1 inhibition mitigates intermittent hypoxia-induced pulmonary hypertension via Dusp1-mediated Erk1/2 deactivation and mitochondrial fission attenuation.\",\"authors\":\"Zhou Pan, Yan Yao, Xu Liu, Yixuan Wang, Xinyue Zhang, Shiqian Zha, Ke Hu\",\"doi\":\"10.1038/s41420-024-02219-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Intermittent hypoxia (IH) precipitates pulmonary vasoconstriction, culminating in the onset of pulmonary hypertension (PH) among individuals afflicted with sleep apnea. While Nuclear receptor subfamily 1 group D member 1 (Nr1d1) is progressively recognized as pivotal regulator of cellular physiology, the role in the pathogenesis of IH-induced PH remains largely uncharted. The expression of Nr1d1 was examined in IH-induced rodent PH and in IH-treated PASMCs. To elucidate the contribution of Nr1d1 to the development of IH-induced PH, we employed siRNA to modulate Nr1d1 expression in vitro and employed serotype 1 adeno-associated virus (AAV1) in vivo. Nr1d1 levels were elevated in IH-induced rodents PH lung tissues and IH-treated PASMCs. Knocking down Nr1d1 by AAV1 effectively inhibited PH progression in chronic IH-induced PH models. Mechanistic investigations identified dual specificity phosphatase 1 (Dusp1), as a direct target that Nr1d1 trans-repressed, mediating Nr1d1's regulatory influence on Erk1/2/Drp1 signaling. Nr1d1 deficiency ameliorates mitochondrial dysfunction and fission by restoring Dusp1 dysregulation and Drp1 phosphorylation. Activation of Erk1/2 with PMA reversed the Dusp1-mediated regulation of Drp1 phosphorylation, indicating the involvement of the Erk1/2 pathway in Drp1 phosphorylation controlled by Dusp1. Meanwhile, intermittent hypoxia induced more severe PH in Dusp1 knockout mice compared with wild-type mice. Our data unveil a novel role for Nr1d1 in IH-induced PH pathogenesis and an undisclosed Nr1d1-Dusp1 axis in PASMCs mitochondrial fission regulation.</p>\",\"PeriodicalId\":9735,\"journal\":{\"name\":\"Cell Death Discovery\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.1000,\"publicationDate\":\"2024-10-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522549/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Death Discovery\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41420-024-02219-5\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death Discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41420-024-02219-5","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
间歇性缺氧(IH)会引起肺血管收缩,最终导致睡眠呼吸暂停患者出现肺动脉高压(PH)。虽然核受体 1 亚家族 D 组 1(Nr1d1)逐渐被认为是细胞生理的关键调节因子,但它在 IH 诱发的 PH 的发病机制中的作用在很大程度上仍是未知数。我们研究了 Nr1d1 在 IH 诱导的啮齿动物 PH 和 IH 处理的 PASMC 中的表达。为了阐明Nr1d1对IH诱导的PH发病的贡献,我们在体外使用siRNA调节Nr1d1的表达,在体内使用血清型1腺相关病毒(AAV1)。在 IH 诱导的啮齿动物 PH 肺组织和经 IH 处理的 PASMCs 中,Nr1d1 水平升高。通过AAV1敲除Nr1d1能有效抑制慢性IH诱导的PH模型的PH进展。机理研究发现,双重特异性磷酸酶1(Dusp1)是Nr1d1反式抑制的直接靶标,它介导了Nr1d1对Erk1/2/Drp1信号转导的调控作用。通过恢复 Dusp1 的失调和 Drp1 的磷酸化,Nr1d1 的缺乏可改善线粒体功能障碍和裂变。用PMA激活Erk1/2可逆转Dusp1介导的Drp1磷酸化调控,表明Erk1/2途径参与了Dusp1控制的Drp1磷酸化。同时,与野生型小鼠相比,间歇性缺氧会诱发Dusp1基因敲除小鼠更严重的PH。我们的数据揭示了 Nr1d1 在 IH 诱导的 PH 发病机制中的新作用,以及在 PASMC 线粒体裂变调控中尚未披露的 Nr1d1-Dusp1 轴。
Nr1d1 inhibition mitigates intermittent hypoxia-induced pulmonary hypertension via Dusp1-mediated Erk1/2 deactivation and mitochondrial fission attenuation.
Intermittent hypoxia (IH) precipitates pulmonary vasoconstriction, culminating in the onset of pulmonary hypertension (PH) among individuals afflicted with sleep apnea. While Nuclear receptor subfamily 1 group D member 1 (Nr1d1) is progressively recognized as pivotal regulator of cellular physiology, the role in the pathogenesis of IH-induced PH remains largely uncharted. The expression of Nr1d1 was examined in IH-induced rodent PH and in IH-treated PASMCs. To elucidate the contribution of Nr1d1 to the development of IH-induced PH, we employed siRNA to modulate Nr1d1 expression in vitro and employed serotype 1 adeno-associated virus (AAV1) in vivo. Nr1d1 levels were elevated in IH-induced rodents PH lung tissues and IH-treated PASMCs. Knocking down Nr1d1 by AAV1 effectively inhibited PH progression in chronic IH-induced PH models. Mechanistic investigations identified dual specificity phosphatase 1 (Dusp1), as a direct target that Nr1d1 trans-repressed, mediating Nr1d1's regulatory influence on Erk1/2/Drp1 signaling. Nr1d1 deficiency ameliorates mitochondrial dysfunction and fission by restoring Dusp1 dysregulation and Drp1 phosphorylation. Activation of Erk1/2 with PMA reversed the Dusp1-mediated regulation of Drp1 phosphorylation, indicating the involvement of the Erk1/2 pathway in Drp1 phosphorylation controlled by Dusp1. Meanwhile, intermittent hypoxia induced more severe PH in Dusp1 knockout mice compared with wild-type mice. Our data unveil a novel role for Nr1d1 in IH-induced PH pathogenesis and an undisclosed Nr1d1-Dusp1 axis in PASMCs mitochondrial fission regulation.
期刊介绍:
Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary.
Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.