HSP22 suppresses diabetes-induced endothelial injury by inhibiting mitochondrial reactive oxygen species formation.
HSP22 suppresses diabetes-induced endothelial injury by inhibiting mitochondrial reactive oxygen species formation.
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HSP22 通过抑制线粒体活性氧的形成来抑制糖尿病引起的内皮损伤
DOI：
10.1016/j.redox.2018.101095
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发表时间：
2019
期刊：
影响因子：
11.4
通讯作者：
Cheng Xiaoshu
中科院分区：
文献类型：
--
作者：
Yu Lingling;Liang Qian;Zhang Weifang;Liao Minqi;Wen Minghua;Zhan Biming;Bao Huihui;Cheng Xiaoshu
高血糖诱导的线粒体活性氧（mtROS）是导致内皮细胞活化和损伤的关键事件。热休克蛋白22（HSP22）是一种与细胞保护和细胞凋亡抑制相关的应激诱导蛋白。然而，HSP22是否能预防高血糖诱导的血管内皮损伤仍不清楚。在这里，我们研究了HSP 22是否通过减少线粒体ROS的产生来保护血管内皮免受高血糖诱导的损伤。我们采用高脂饮食和链脲佐菌素注射模型诱导2型糖尿病（T2DM，代谢综合征），并将HSP22过表达或沉默的人脐静脉内皮细胞（HUVECs）暴露于高糖环境中，以探讨HSP22的作用。我们发现，热休克蛋白22显着抑制内皮细胞活化和血管病变抑制内皮细胞粘附和减少细胞因子的分泌。我们进行了共聚焦显微镜和流式细胞术分析，使用HUVECs，并表明热休克蛋白22衰减高血糖刺激的内皮细胞线粒体活性氧和线粒体功能障碍。从机制上讲，使用mtROS抑制剂MitoTEMPO，我们证明了HSP 22通过消除高血糖介导的mtROS增加来抑制内皮活化和损伤。此外，我们还发现HSP 22在体外通过减轻线粒体ROS来维持线粒体融合和分裂的平衡。在T2DM小鼠模型中，HSP 22通过抑制线粒体ROS介导的内皮激活来减轻血管病变的发展。这项研究提供了证据表明，热休克蛋白22可能是一个有前途的治疗靶点血管并发症的2型糖尿病。
The induction of mitochondrial reactive oxygen species (mtROS) by hyperglycemia is a key event responsible for endothelial activation and injury. Heat shock protein 22 (HSP22) is a stress-inducible protein associated with cytoprotection and apoptosis inhibition. However, whether HSP22 prevents hyperglycemia-induced vascular endothelial injury remains unclear. Here, we investigated whether HSP22 protects the vascular endothelium from hyperglycemia-induced injury by reducing mtROS production. We used a high-fat diet and streptozotocin injection model to induce type 2 diabetes mellitus (T2DM, metabolic syndrome) and exposed human umbilical vein endothelial cells (HUVECs) to high glucose following overexpression or silencing of HSP22 to explore the role of HSP22. We found that HSP22 markedly inhibited endothelial cell activation and vascular lesions by inhibiting endothelial adhesion and decreasing cytokine secretion. We performed confocal microscopy and flow cytometry assays using HUVECs and showed that HSP22 attenuated mtROS and mitochondrial dysfunction in hyperglycemia-stimulated endothelial cells. Mechanistically, using the mtROS inhibitor MitoTEMPO, we demonstrated that HSP22 suppressed endothelial activation and injury by eliminating hyperglycemia-mediated increases in mtROS. Furthermore, we found that HSP22 maintained the balance of mitochondrial fusion and fission by mitigating mtROSin vitro. HSP22 attenuated the development of vascular lesions by suppressing mtROS-mediated endothelial activation in a T2DM mouse model. This study provides evidence that HSP22 may be a promising therapeutic target for vascular complications in T2DM.