Heme Oxygenase-1 at the Nexus of Endothelial Cell Fate Decision Under Oxidative Stress.
Heme Oxygenase-1 at the Nexus of Endothelial Cell Fate Decision Under Oxidative Stress.
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DOI：
10.3389/fcell.2021.702974
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发表时间：
2021
影响因子：
5.5
通讯作者：
Subramaniam S
中科院分区：
文献类型：
--
作者：
Raghunandan S;Ramachandran S;Ke E;Miao Y;Lal R;Chen ZB;Subramaniam S
内皮细胞 (EC) 形成血管内壁，对于感知可能导致氧化应激的化学扰动至关重要。压力程度与不同的表型相关，例如静止、细胞死亡或衰老。每种可能的细胞命运都与内皮功能的不同方面相关，因此，细胞命运决定的调节对于维持血管健康至关重要。本研究通过纵向测量（包括细胞、基因表达和扰动测量）检查了人类 EC 在细胞存活和死亡边界处的氧化应激反应 (OSR)。 0.5 mM 过氧化氢 (HP) 产生显着的氧化应激，将细胞置于该连接处，并提供了研究细胞命运效应器的模型。使用系统扰动和高通量测量可以深入了解应激反应的多种状态。使用系统方法，我们破译了这些机制的分子机制。值得注意的是，我们的研究表明血红素加氧酶-1 (HMOX1) 充当细胞命运决定的看门人。具体来说，当单独用 HP 处理时，HP 对 HMOX1 敲低细胞的处理逆转了 2,892 个差异表达基因中约 51% 的基因表达，影响了多种细胞过程，包括抗氧化反应、炎症、DNA 损伤和修复、细胞周期和生长、线粒体应激、代谢应激和自噬。进一步的分析表明，这些转换基因在三个空间位置高度富集，即细胞表面、线粒体和细胞核。特别是，它揭示了 HMOX1 对细胞表面受体 EGFR 和 IGFR、线粒体 ETC（MTND3、MTATP6）的新作用，以及通过染色质修饰剂（KDM6A、RBBP5 和 PPM1D）和长非编码 RNA（lncRNA）在细胞生存和死亡边界协调细胞命运的表观遗传调控。这些新颖的方面表明 HMOX1 可以影响转录和表观遗传调节，从而协调影响细胞命运决策的 OSR。
Endothelial cells (ECs) form the inner lining of blood vessels and are central to sensing chemical perturbations that can lead to oxidative stress. The degree of stress is correlated with divergent phenotypes such as quiescence, cell death, or senescence. Each possible cell fate is relevant for a different aspect of endothelial function, and hence, the regulation of cell fate decisions is critically important in maintaining vascular health. This study examined the oxidative stress response (OSR) in human ECs at the boundary of cell survival and death through longitudinal measurements, including cellular, gene expression, and perturbation measurements. 0.5 mM hydrogen peroxide (HP) produced significant oxidative stress, placed the cell at this junction, and provided a model to study the effectors of cell fate. The use of systematic perturbations and high-throughput measurements provide insights into multiple regimes of the stress response. Using a systems approach, we decipher molecular mechanisms across these regimes. Significantly, our study shows that heme oxygenase-1 (HMOX1) acts as a gatekeeper of cell fate decisions. Specifically, HP treatment of HMOX1 knockdown cells reversed the gene expression of about 51% of 2,892 differentially expressed genes when treated with HP alone, affecting a variety of cellular processes, including anti-oxidant response, inflammation, DNA injury and repair, cell cycle and growth, mitochondrial stress, metabolic stress, and autophagy. Further analysis revealed that these switched genes were highly enriched in three spatial locations viz., cell surface, mitochondria, and nucleus. In particular, it revealed the novel roles of HMOX1 on cell surface receptors EGFR and IGFR, mitochondrial ETCs (MTND3, MTATP6), and epigenetic regulation through chromatin modifiers (KDM6A, RBBP5, and PPM1D) and long non-coding RNA (lncRNAs) in orchestrating the cell fate at the boundary of cell survival and death. These novel aspects suggest that HMOX1 can influence transcriptional and epigenetic modulations to orchestrate OSR affecting cell fate decisions.
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影响因子：
20.1
作者：
Gimbrone MA Jr;García-Cardeña G
通讯作者：
García-Cardeña G
影响因子：
20.1
作者：
Du, J;Brink, M;Delafontaine, P
通讯作者：
Delafontaine, P
影响因子：
4.8
作者：
Biswas, Chhanda;Shah, Nidhi;Dennery, Phyllis A.
通讯作者：
Dennery, Phyllis A.
DOI：
10.1161/01.atv.11.6.1700
发表时间：
1991-11-01
期刊：
ARTERIOSCLEROSIS AND THROMBOSIS
影响因子：
--
作者：
BALLA, G;JACOB, HS;VERCELLOTTI, GM
通讯作者：
VERCELLOTTI, GM
影响因子：
33.6
作者：
Chiu JJ;Chien S
通讯作者：
Chien S