Mesenchymal stem cells ameliorate hyperglycemia-induced endothelial injury through modulation of mitophagy.
Mesenchymal stem cells ameliorate hyperglycemia-induced endothelial injury through modulation of mitophagy.
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间充质干细胞通过调节线粒体自噬改善高血糖诱导的内皮损伤
DOI：
10.1038/s41419-018-0861-x
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发表时间：
2018-08-06
影响因子：
9
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Zhu W;Yuan Y;Liao G;Li L;Liu J;Chen Y;Zhang J;Cheng J;Lu Y
线粒体功能障碍以及过量的线粒体活性氧（ROS）是糖尿病状态下内皮损伤的根本原因。间充质干细胞（MSCs）展现出了非凡的细胞保护作用，这种作用延伸到对线粒体稳态的调节。然而，其潜在机制尚未明确界定。新出现的证据表明，线粒体自噬可通过选择性清除受损或功能失调的线粒体来抵消线粒体衍生的氧化应激。因此，我们研究了间充质干细胞是否可通过调节线粒体自噬来改善高糖诱导的内皮损伤。我们观察到，将人脐静脉内皮细胞（HUVECs）暴露于高糖环境会引发线粒体损伤，表现为线粒体过度碎片化和ROS产生、膜电位丧失以及ATP生成减少。此外，高糖损伤会削弱线粒体自噬，这加速了功能失调的线粒体积累，启动线粒体凋亡途径，并最终导致内皮功能障碍。间充质干细胞治疗显著减轻了这些扰动，同时伴有Pink1和Parkin表达的增强，然而当Pink1或Parkin被敲低时，间充质干细胞的这些有益作用就会消失。在糖尿病大鼠的主动脉中，观察到线粒体自噬缺陷，这与明显的线粒体功能障碍同时发生。在超微结构上，来自糖尿病大鼠的肾动脉内皮细胞（RAECs）显示出自噬泡显著减少以及碎片化线粒体显著增加。重要的是，间充质干细胞的输注恢复了Pink1/Parkin介导的线粒体自噬，改善了线粒体功能障碍，并减轻了糖尿病大鼠内皮细胞的凋亡。这些结果表明，间充质干细胞可能通过Pink1/Parkin介导的线粒体自噬来改善线粒体功能障碍，从而保护内皮细胞免受高血糖诱导的损伤。
Mitochondrial dysfunction and excessive mitochondrial reactive oxygen species (ROS) are fundamental contributors to endothelial injury in diabetic states. Mesenchymal stem cells (MSCs) have exhibited an extraordinary cytoprotective effect that extends to the modulation of mitochondrial homeostasis. However, the underlying mechanisms have not been clearly defined. Emerging evidence has suggested that mitophagy could counteract mitochondrial-derived oxidative stress through the selective elimination of impaired or dysfunctional mitochondria. Therefore, we investigated whether MSCs could ameliorate high-glucose-induced endothelial injury through the modulation of mitophagy. We observed that exposure of human umbilical vein endothelial cells (HUVECs) to high glucose triggers mitochondrial impairment with excessive mitochondrial fragmentation and ROS generation, loss of membrane potential and reduced ATP production. Furthermore, mitophagy was blunted upon high glucose insult, which accelerated dysfunctional mitochondrial accumulation, initiating the mitochondrial apoptotic pathway and, eventually, endothelial dysfunction. MSCs treatment notably attenuated these perturbations accompanied by an enhancement of Pink1 and Parkin expression, whereas these beneficial effects of MSCs were abolished when either Pink1 or Parkin was knocked down. In aortas of diabetic rats, defective mitophagy was observed, which coincided with marked mitochondrial dysfunction. Ultrastructurally, RAECs from diabetic rats revealed a significant reduction in autophagic vacuoles and a marked increase in fragmented mitochondria. Importantly, the infusion of MSCs restored Pink1/Parkin-mediated mitophagy, ameliorated mitochondrial dysfunction and attenuated apoptosis in endothelial cells in diabetic rats. These results suggest that MSCs may protect endothelial cells from hyperglycemia-induced injury by ameliorating mitochondrial dysfunction via Pink1/Parkin –mediated mitophagy
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影响因子：
7.7
作者：
Jurewicz M;Yang S;Augello A;Godwin JG;Moore RF;Azzi J;Fiorina P;Atkinson M;Sayegh MH;Abdi R
通讯作者：
Abdi R
影响因子：
37.8
作者：
Shenouda SM;Widlansky ME;Chen K;Xu G;Holbrook M;Tabit CE;Hamburg NM;Frame AA;Caiano TL;Kluge MA;Duess MA;Levit A;Kim B;Hartman ML;Joseph L;Shirihai OS;Vita JA
通讯作者：
Vita JA
DOI：
10.1042/bj20111451
发表时间：
2012-01-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Lee J;Giordano S;Zhang J
通讯作者：
Zhang J
影响因子：
12.4
作者：
Michiorri, S.;Gelmetti, V.;Casari, G.
通讯作者：
Casari, G.
影响因子：
13.6
作者：
Ayanga, Bernard A.;Badal, Shawn S.;Danesh, Farhad R.
通讯作者：
Danesh, Farhad R.