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Hypoxia-induced mitochondrial reactive oxygen species (mtROS) differentially regulates proliferation of smooth muscle cells (SMCs) of the pulmonary and systemic vasculature
Mitochondrion ( IF 3.9 ) Pub Date : 2021-03-01 , DOI: 10.1016/j.mito.2020.11.012 Shipra Bhansali 1 , Kamal Sohi 2 , Veena Dhawan 2
Mitochondrion ( IF 3.9 ) Pub Date : 2021-03-01 , DOI: 10.1016/j.mito.2020.11.012 Shipra Bhansali 1 , Kamal Sohi 2 , Veena Dhawan 2
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BACKGROUND
Vascular remodeling plays a pivotal role in regulating hypoxia-mediated pulmonary and systemic hypertension via the phenotypic modulation of smooth muscle cells (SMCs) of pulmonary and systemic arteries. Mitochondria serve as putative oxygen (O2) sensors, and consequently, adaptations to hypoxia are mediated via HIF (hypoxia-inducible factors) activation, which impinges on mitochondrial function by suppressing the mitochondrial activity. Therefore, we explored the implication of hypoxia-mediated mitochondrial stress in pulmonary and systemic arterial remodeling. METHODS
The hypoxic (10% O2) effect on human pulmonary artery and aortic SMCs was examined in vitro by cell viability assay, proliferation index, autophagy, and comet assays. Mitochondrial ROS (mtROS), membrane potential (MMP), and mitochondrial morphology were assessed using mitochondrial-selective fluorescent probes. Further, the cell cycle distribution was analyzed by flow cytometry using propidium iodide staining. RESULTS
Our data indicate no significant alterations in cell viability and active proliferation of hypoxic PASMCs; however, an excessive rise in mtROS production and disrupted MMP, accompanied by enhanced DNA damage and reduced autophagy was observed, highlighting the 'apoptosis resistance' phenotype in these cells. Conversely, in hypoxia-treated hASMCs, a modest rise in mtROS levels was associated with reduced DNA damage; followed by upregulated autophagy; increased S-phase DNA content and cell viability, depicting the cytoprotective effect of hypoxia-induced autophagy against mitochondrial damage in hASMCs. CONCLUSION
Our findings suggest that differential impact of mtROS on proliferative capacity may contribute to the variable hypoxic responses in pulmonary and systemic vasculature. Therefore, targeting mtROS may serve as an effective therapeutic strategy to prevent hypoxia-induced hypertension.
中文翻译：
缺氧诱导的线粒体活性氧 (mtROS) 差异调节肺和全身血管平滑肌细胞 (SMC) 的增殖
背景血管重塑通过肺和全身动脉的平滑肌细胞(SMC)的表型调节在调节缺氧介导的肺和全身性高血压中起关键作用。线粒体充当假定的氧 (O2) 传感器，因此，对缺氧的适应是通过 HIF（缺氧诱导因子）激活介导的，这通过抑制线粒体活性来影响线粒体功能。因此，我们探讨了缺氧介导的线粒体应激在肺和全身动脉重塑中的意义。方法通过细胞活力测定、增殖指数、自噬和彗星测定在体外检查缺氧（10% O2）对人肺动脉和主动脉SMC的影响。线粒体活性氧 (mtROS)、膜电位 (MMP)、使用线粒体选择性荧光探针评估线粒体形态。此外，使用碘化丙啶染色通过流式细胞术分析细胞周期分布。结果 我们的数据表明细胞活力和缺氧 PASMC 的活跃增殖没有显着改变；然而，观察到 mtROS 产生过度增加和 MMP 破坏，伴随着 DNA 损伤增强和自噬减少，突出了这些细胞中的“细胞凋亡抗性”表型。相反，在缺氧处理的 hASMC 中，mtROS 水平的适度上升与 DNA 损伤的减少有关。随后是上调的自噬；S 期 DNA 含量和细胞活力增加，描述了缺氧诱导的自噬对 hASMC 线粒体损伤的细胞保护作用。结论我们的研究结果表明，mtROS 对增殖能力的不同影响可能导致肺和全身脉管系统的不同缺氧反应。因此，靶向 mtROS 可作为预防缺氧性高血压的有效治疗策略。
更新日期：2021-03-01
中文翻译：
缺氧诱导的线粒体活性氧 (mtROS) 差异调节肺和全身血管平滑肌细胞 (SMC) 的增殖
背景血管重塑通过肺和全身动脉的平滑肌细胞(SMC)的表型调节在调节缺氧介导的肺和全身性高血压中起关键作用。线粒体充当假定的氧 (O2) 传感器，因此，对缺氧的适应是通过 HIF（缺氧诱导因子）激活介导的，这通过抑制线粒体活性来影响线粒体功能。因此，我们探讨了缺氧介导的线粒体应激在肺和全身动脉重塑中的意义。方法通过细胞活力测定、增殖指数、自噬和彗星测定在体外检查缺氧（10% O2）对人肺动脉和主动脉SMC的影响。线粒体活性氧 (mtROS)、膜电位 (MMP)、使用线粒体选择性荧光探针评估线粒体形态。此外，使用碘化丙啶染色通过流式细胞术分析细胞周期分布。结果 我们的数据表明细胞活力和缺氧 PASMC 的活跃增殖没有显着改变；然而，观察到 mtROS 产生过度增加和 MMP 破坏，伴随着 DNA 损伤增强和自噬减少，突出了这些细胞中的“细胞凋亡抗性”表型。相反，在缺氧处理的 hASMC 中，mtROS 水平的适度上升与 DNA 损伤的减少有关。随后是上调的自噬；S 期 DNA 含量和细胞活力增加，描述了缺氧诱导的自噬对 hASMC 线粒体损伤的细胞保护作用。结论我们的研究结果表明，mtROS 对增殖能力的不同影响可能导致肺和全身脉管系统的不同缺氧反应。因此，靶向 mtROS 可作为预防缺氧性高血压的有效治疗策略。
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