Inhibition of IP3R3 attenuates endothelial to mesenchymal transition induced by TGF-β1 through restoring mitochondrial function.
Inhibition of IP3R3 attenuates endothelial to mesenchymal transition induced by TGF-β1 through restoring mitochondrial function.
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DOI：
10.1016/j.bbrc.2022.06.033
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发表时间：
2022-06
影响因子：
3.1
通讯作者：
Yahang Xu;Xinyue Guo;S. Ning;Q. He;Bingran Meng;Fu-shan Xing;Yupeng Yin
中科院分区：
文献类型：
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作者：
Yahang Xu;Xinyue Guo;S. Ning;Q. He;Bingran Meng;Fu-shan Xing;Yupeng Yin
肺动脉高压(PAH)是一种以肺动脉压升高和右室肥厚为特征的进展性疾病。肌醇1，4，5-三磷酸受体(IP3Rs)从内质网释放钙离子，调节内皮细胞的通透性和迁移，从而影响PAH。本研究检测了肺高压大鼠肺组织中IP3R3的表达水平及其在肺组织中的定位，并观察了IP3R3对内皮细胞向间充质转化及转化生长因子-β-1处理后内皮细胞线粒体功能的影响。抑制IP3R3可降低EndMT标志物、细胞迁移、ROS生成、钙离子水平，增加线粒体膜电位和线粒体呼吸链复合体I、III和V的活性。这些结果表明，抑制IP3R3可通过恢复线粒体功能来减弱转化生长因子-β-1诱导的EndMT和迁移，从而为治疗肺动脉高压提供了新的机会。
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary artery pressure and right ventricular hypertrophy. Inositol 1,4,5-trisphosphate receptors (IP3Rs) release calcium ions from the endoplasmic reticulum to regulate permeability and migration of endothelial, thereby affecting PAH. In this study, We determined the expression level of IP3R3 and its position in lung tissue from PAH rat models, and stud the effect of IP3R3 on endothelial to mesenchymal transition (EndMT) and mitochondrial function of endothelial cells treated with TGF-β1. We observed that IP3R3 was significantly overexpressed in the lung tissues from PAH rat models. Inhibition of IP3R3 reduced EndMT markers, cell migration, ROS production, Ca2+levels, increased mitochondrial membrane potential and mitochondrial respiratory chain complex I, III, and V activities. These results suggest that the inhibition of IP3R3 attenuated EndMT and migration induced by TGF-β1 via restoring of mitochondrial functions, thereby suggesting a novel therapeutic opportunity for PAH.