Notch3/Hes5 Induces Vascular Dysfunction in Hypoxia-Induced Pulmonary Hypertension Through ER Stress and Redox-Sensitive Pathways.
Notch3/Hes5 Induces Vascular Dysfunction in Hypoxia-Induced Pulmonary Hypertension Through ER Stress and Redox-Sensitive Pathways.
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DOI：
10.1161/hypertensionaha.122.20449
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发表时间：
2023-08
期刊：
影响因子：
--
通讯作者：
Touyz RM
中科院分区：
文献类型：
--
作者：
Morris HE;Neves KB;Nilsen M;Montezano AC;MacLean MR;Touyz RM
Notch 3（神经源性位点notch同源蛋白3）与血管疾病有关，包括肺动脉高压（PH）/肺动脉高压。然而，分子机制仍然难以捉摸。我们假设增加的Notch 3激活诱导氧化和内质网（ER）应激和下游氧化还原信号传导，与促收缩肺动脉状态，肺血管功能障碍和PH发展相关。在暴露于慢性缺氧以诱导PH的TgNotch 3R 169 C小鼠（携带功能获得性[GOF] Notch 3突变）中进行研究，并通过血流动力学检查。对肺动脉高压患者的肺动脉平滑肌细胞和小鼠肺进行了分子和细胞研究。测量Notch 3调节的基因/蛋白、ER应激、ROCK（Rho相关激酶）表达/活性、Ca 2+瞬变和活性氧簇的产生以及一氧化氮。在法舒地尔（ROCK抑制剂）和4-苯基丁酸（ER应激抑制剂）存在下评估肺血管反应性。与对照相比，缺氧在TgNotch 3R 169 C小鼠中诱导更严重的PH表型。TgNotch 3R 169 C小鼠表现出增强的Notch 3活化和Notch 3靶点Hes家族BHLH转录因子5（Hes 5）的表达，具有增加的血管收缩和受损的血管舒张，其用法舒地尔/4-苯基丁酸改善。Notch 3突变与肺血管Ca 2+瞬变增加、ROCK激活、ER应激和活性氧产生增加、NO产生减少和sGC（可溶性鸟苷酸环化酶）/cGMP信号转导减弱相关。N-乙酰半胱氨酸可改善这些效应。来自肺动脉高压患者的肺动脉平滑肌细胞重现了在PH小鼠中观察到的Notch 3/Hes 5信号传导、ER应激和氧化还原变化。Notch 3 GOF放大缺氧PH中的血管功能障碍。这涉及氧化和ER应激以及ROCK。我们强调了Notch 3/Hes 5-氧化还原信号的新作用，以及ER和氧化应激在PH中的重要相互作用。
Notch3 (neurogenic locus notch homolog protein 3) is implicated in vascular diseases, including pulmonary hypertension (PH)/pulmonary arterial hypertension. However, molecular mechanisms remain elusive. We hypothesized increased Notch3 activation induces oxidative and endoplasmic reticulum (ER) stress and downstream redox signaling, associated with procontractile pulmonary artery state, pulmonary vascular dysfunction, and PH development. Studies were performed in TgNotch3R169C mice (harboring gain-of-function [GOF] Notch3 mutation) exposed to chronic hypoxia to induce PH, and examined by hemodynamics. Molecular and cellular studies were performed in pulmonary artery smooth muscle cells from pulmonary arterial hypertension patients and in mouse lung. Notch3-regulated genes/proteins, ER stress, ROCK (Rho-associated kinase) expression/activity, Ca2+ transients and generation of reactive oxygen species, and nitric oxide were measured. Pulmonary vascular reactivity was assessed in the presence of fasudil (ROCK inhibitor) and 4-phenylbutyric acid (ER stress inhibitor). Hypoxia induced a more severe PH phenotype in TgNotch3R169C mice versus controls. TgNotch3R169C mice exhibited enhanced Notch3 activation and expression of Notch3 targets Hes Family BHLH Transcription Factor 5 (Hes5), with increased vascular contraction and impaired vasorelaxation that improved with fasudil/4-phenylbutyric acid. Notch3 mutation was associated with increased pulmonary vessel Ca2+ transients, ROCK activation, ER stress, and increased reactive oxygen species generation, with reduced NO generation and blunted sGC (soluble guanylyl cyclase)/cGMP signaling. These effects were ameliorated by N-acetylcysteine. pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension recapitulated Notch3/Hes5 signaling, ER stress and redox changes observed in PH mice. Notch3 GOF amplifies vascular dysfunction in hypoxic PH. This involves oxidative and ER stress, and ROCK. We highlight a novel role for Notch3/Hes5-redox signaling and important interplay between ER and oxidative stress in PH.
影响因子：
--
作者：
Jaitovich A;Jourd'heuil D
通讯作者：
Jourd'heuil D
影响因子：
2.6
作者：
Padhye, Akhilesh A.;Sahay, Sandeep
通讯作者：
Sahay, Sandeep