Hypoxia promotes pulmonary vascular remodeling via HIF-1α to regulate mitochondrial dynamics
Hypoxia promotes pulmonary vascular remodeling via HIF-1α to regulate mitochondrial dynamics
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DOI：
10.11909/j.issn.1671-5411.2019.12.003
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发表时间：
2019-01-01
影响因子：
2.5
通讯作者：
Zhong, Guang-Wei
中科院分区：
文献类型：
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作者：
Chen, Xi;Yao, Jia-Mei;Zhong, Guang-Wei
背景越来越多的研究表明线粒体缺陷在肺动脉高压（PH）的发病中起重要作用。线粒体动力学和质量控制在维持细胞增殖和凋亡平衡中具有核心作用。然而，这种平衡的分子机制仍然是未知的。方法在低氧条件下培养大鼠肺动脉平滑肌细胞（PASMC），观察缺氧诱导因子-1 α（HIF-1 α）对PASMC和肺动脉高压大鼠的生物学效应。细胞活力，活性氧水平，细胞死亡，线粒体形态，线粒体膜电位，线粒体功能和线粒体生物合成，以及分裂和融合相关蛋白，在缺氧条件下进行测量。另外，在低氧条件下维持大鼠，检查并记录右心室收缩压、右心室肥厚指数和右心室重量/体重比。此外，我们评估了HIF-1 α在PH的发展和进展中的作用，使用HIF-1 α基因敲低，使用小干扰RNA转染。在缺氧前进行Mdivi-1处理以抑制动力蛋白相关蛋白1（Drp 1）。结果缺氧时HIF-1 α表达增加，HIF-1 α表达增加与缺氧诱导的线粒体功能障碍及缺氧刺激的PASMCs增殖和凋亡有关。我们还发现，通过线粒体分裂抑制剂Mdivi-1靶向线粒体分裂Drp 1在PH模型大鼠中是有效的。结果表明，线粒体动力学参与了缺氧肺血管重建过程。此外，HIF-1 α还通过直接调节Drp 1的表达来调节缺氧条件下肺血管重构中的线粒体动力学。结论线粒体动力学异常可作为PH早期诊断和监测病情进展的指标。需要进一步研究PH中控制线粒体分裂/融合的信号通路。
Background Increasing research suggests that mitochondrial defect plays a major role in pulmonary hypertension (PH) pathogenesis. Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation and apoptosis balance. However, the molecular mechanism underlying of this balance is still unknown. Methods To clarify the biological effects of hypoxic air exposure and hypoxia-inducible factor-1 alpha (HIF-1 alpha) on pulmonary arterial smooth muscle cell (PASMC) and pulmonary arterial hypertension rats, the cells were cultured in a hypoxic chamber under oxygen concentrations. Cell viability, reactive oxygen species level, cell death, mitochondrial morphology, mitochondrial membrane potential, mitochondrial function and mitochondrial biosynthesis, as well as fission-and fusion-related proteins, were measured under hypoxic conditions. In addition, rats were maintained under hypoxic conditions, and the right ventricular systolic pressure, right ventricular hypertrophy index and right ventricular weight/body weight ratio were examined and recorded. Further, we assessed the role of HIF-1 alpha in the development and progression of PH using HIF-1 alpha gene knockdown using small interfering RNA transfection. Mdivi-1 treatment was performed before hypoxia to inhibit dynamin-related protein 1 (Drp1). Results We found that HIF-1 alpha expression was increased during hypoxia, which was crucial for hypoxia-induced mitochondrial dysfunction and hypoxia-stimulated PASMCs proliferation and apoptosis. We also found that targeting mitochondrial fission Drp1 by mitochondrial division inhibitor Mdivi-1 was effective in PH model rats. The results showed that mitochondrial dynamics were involved in the pulmonary vascular remodeling under hypoxia in vivo and in vitro. Furthermore, HIF-1 alpha also modulated mitochondrial dynamics in pulmonary vascular remodeling under hypoxia through directly regulating the expression of Drp1. Conclusions In conclusion, our data suggests that abnormal mitochondrial dynamics could be a marker for the early diagnosis of PH and monitoring disease progression. Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in PH.