Disruption of the superoxide anions-mitophagy regulation axis mediates copper oxide nanoparticles-induced vascul)ar endothelial cell death.
Disruption of the superoxide anions-mitophagy regulation axis mediates copper oxide nanoparticles-induced vascul)ar endothelial cell death.
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超氧阴离子线粒体自噬调节轴的破坏介导氧化铜纳米颗粒诱导的血管内皮细胞死亡。
DOI：
10.1016/j.freeradbiomed.2018.09.032
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发表时间：
2018
影响因子：
7.4
通讯作者：
Yu Chao
中科院分区：
文献类型：
--
作者：
Zhang jun;Wang Bin;Wang Hong;He Hui;Wu Qiong;Qin Xia;Yang Xi;Chen Linmu;Yuan Zhiyi;Yi Qiying;Zou Zhen;Yu Chao
氧化铜纳米颗粒（CuONP）在工业和医药领域有着广泛的应用，但其毒性却备受关注。目前，纳米材料对心血管系统的毒性正受到越来越多的关注。我们以前的毒理学研究发现，溶酶体沉积的CuONP触发血管内皮细胞死亡，表明自噬功能障碍的参与是至关重要的CuONP诱导的毒性在人脐静脉内皮细胞（HUVECs）。在目前的研究中，我们调查的详细机制的自噬功能障碍诱导的铜ONP。我们证明，CuONPs暴露引起超氧阴离子的积累，这可能是由于线粒体功能障碍。MnTBAP是一种超氧阴离子清除剂，可减轻CuONPs诱导的HUVECs死亡，表明过量的超氧阴离子与CuONPs对HUVECs的细胞毒性直接相关。有趣的是，我们发现线粒体自噬（一种清除受损线粒体和过量超氧阴离子的保护机制）在CuONP处理的细胞中被启动，但未能被清除，导致受损线粒体的积累。通过Atg 5敲除或用Mdivi-1阻断线粒体分裂来抑制线粒体自噬显著加重CuONP诱导的超氧阴离子积累和细胞死亡，表明线粒体自噬是对CuONP细胞毒性的保护机制。总之，我们证明，超氧阴离子（来自受损的线粒体）参与CuONPs相关的毒性和受损的mitophagic通量的积累过量的超氧阴离子，导致HUVEC死亡。我们的研究结果表明，超氧阴离子和线粒体自噬在CuONP诱导的血管内皮细胞毒性中起着至关重要的作用。
Copper oxide nanoparticles (CuONPs) have been widely used in the industrial and pharmaceutical fields; however, their toxicity profile is deeply concerning. Currently, nanomaterials-induced toxicity in the cardiovascular system is receiving increased attention. Our previous toxicological study found that lysosomal deposition of CuONPs triggered vascular endothelial cell death, indicating that the involvement of autophagic dysfunction was crucial for CuONPs-induced toxicity in human umbilical vein endothelial cells (HUVECs). In the current study, we investigated the detailed mechanism underlying the autophagic dysfunction induced by CuONPs. We demonstrated that CuONPs exposure caused accumulation of superoxide anions, which likely resulted from mitochondrial dysfunctions. MnTBAP, a superoxide anions scavenger, alleviated CuONPs-induced HUVECs death, indicating that excessive superoxide anions were directly related to the CuONPs cytotoxicity in HUVECs. Interestingly, we found that mitophagy (a protective mechanism for clearance of damaged mitochondria and excessive superoxide anions) was initiated but failed to be cleared in CuONPs-treated cells, resulting in the accumulation of damaged mitochondria. Inhibition of mitophagy through Atg5 knockout or blocking of mitochondria fission with Mdivi-1 significantly aggravated CuONPs-induced superoxide anions accumulation and cell death, suggesting that mitophagy is a protective mechanism against CuONPs cytotoxicity in HUVECs. In summary, we demonstrate that superoxide anions (originating from damaged mitochondria) are involved in CuONPs-associated toxicity and that impaired mitophagic flux aggravates the accumulation of excessive superoxide anions, which leads to HUVECs death. Our findings indicate that there are crucial roles for superoxide anions and mitophagy in CuONPs-induced toxicity in vascular endothelial cells.