Salubrinal attenuates right ventricular hypertrophy and dysfunction in hypoxic pulmonary hypertension of rats
Salubrinal attenuates right ventricular hypertrophy and dysfunction in hypoxic pulmonary hypertension of rats
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DOI：
10.1016/j.vph.2016.09.009
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发表时间：
2016-12-01
影响因子：
4
通讯作者：
He, Kun-Lun
中科院分区：
文献类型：
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作者：
He, Yun-Yun;Liu, Chun-Lei;He, Kun-Lun
真核翻译起始因子2 α（p-eIF2 α）的磷酸化对于缺氧期间的细胞存活是必不可少的。本研究的目的是探讨salubrinal，p-eIF2 α去磷酸化抑制剂是否可以减轻低压缺氧大鼠肺动脉高压（PAH）和右心室（RV）肥大。采用低压缺氧法建立大鼠肺动脉高压模型。在预防方案或逆转方案中，补充Salubrinal是随机的。在随访结束时，我们测量了超声心动图、血液动力学、苏木素-伊红和Masson三色染色。探索RNA-seq分析以鉴定与有或没有salubrinal的低压缺氧相关的基因表达的变化。与暴露于低压缺氧的溶剂处理大鼠相比，salubrinal防止并部分逆转了平均肺动脉压和RV肥大的增加。salubrinal在预防和逆转治疗中均能降低肺动脉壁厚度百分比（WT %）和RV胶原体积分数（CVF）。我们还发现salubrinal能够降低内质网应激和氧化应激。RNA-seq分析结果显示，慢性低氧刺激了细胞周期调控、心室肥厚等一系列基因的差异表达，其中一些基因可被salubrinal改善。这些结果表明，salubrinal可以防止和逆转建立RV重塑，并恢复暴露于低压缺氧的大鼠右心室中改变的基因和通路。(C)2016由Elsevier Inc.出版
The phosphorylation of eulcaryotic translation initiation factor 2 alpha (p-eIF2 alpha) is essential for cell survival during hypoxia. The aim of this study was to investigate whether salubrinal, an inhibitor of p-eIF2 alpha dephosphorylation could attenuate pulmonary arterial hypertension (PAH) and right ventricular (RV) hypertrophy in rats exposed to hypobaric hypoxia. PAH of rats was induced by hypobaric hypoxia. Salubrinal supplemented was randomized in either a prevention or a reversal protocol. At the end of the follow-up point, we measured echo-cardiography, hemodynamics, hematoxylin-eosin and Masson's trichrome stainings. RNA-seq analysis is explored to identify changes in gene expression associated with hypobaric hypoxia with or without salubrinal. Compared with vehicle-treatment rats exposed to hypobaric hypoxia, salubrinal prevented and partly reversed the increase of the mean pulmonary artery pressure and RV hypertrophy. What's more, salubrinal reduced the percentage wall thickness (WT%) of pulmonary artery and RV collagen volume fraction (CVF) in both prevention and reversal protocols. We also found that salubrinal was capable of reducing endoplasmic reticulum stress and oxidative stress. The result of RNA-seq analysis revealed that chronic hypoxia stimulated the differential expression of a series of genes involved in cell cycle regulation and ventricular hypertrophy and so on. Some of these genes could be ameliorated by salubrinal. These results indicate that salubrinal could prevent and reverse well-established RV remodeling, and restore the genes and pathways altered in the right ventricles of rats exposed to hypobaric hypoxia. (C) 2016 Published by Elsevier Inc.