Clusterin ameliorates endothelial dysfunction in diabetes by suppressing mitochondrial fragmentation
Clusterin ameliorates endothelial dysfunction in diabetes by suppressing mitochondrial fragmentation
复制标题
簇蛋白通过抑制线粒体碎片改善糖尿病内皮功能障碍
DOI：
10.1016/j.freeradbiomed.2019.10.008
复制
发表时间：
2019-12-01
影响因子：
7.4
通讯作者：
Liu, Lihong
中科院分区：
文献类型：
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作者：
Ren, Lulu;Han, Feifei;Liu, Lihong
簇蛋白 (CLU) 是一种应激反应蛋白，与多种病理过程中的细胞保护相关。然而，簇蛋白在糖尿病引起的内皮功能障碍中的功能尚未明确。在此，我们使用两种糖尿病模型，研究了凝聚素在糖尿病引发的内皮功能障碍中的作用及其分子机制。结果表明，在 db/db 糖尿病小鼠和链脲佐菌素 (STZ) 诱导的糖尿病模型中，簇蛋白过度表达可抑制主动脉中 ICAM-1/VCAM-1 的表达，并改善内皮依赖性血管舒张。一致地，在体外，腺病毒簇蛋白过度表达降低了一系列促炎细胞因子的表达，并抑制单核细胞与经历高葡萄糖和高棕榈酸盐的内皮细胞的粘附。进一步的研究表明，簇蛋白过度表达可以减轻线粒体过度分裂并减少线粒体 ROS 的产生。相反，沉默簇蛋白会加剧高糖暴露内皮细胞中的线粒体分裂和内皮炎症激活。越来越多的证据表明，线粒体动力学受损在促进糖尿病受试者内皮功能障碍方面发挥着相当大的作用。因此，针对线粒体过度分裂的治疗可能是预防糖尿病血管并发症的有希望的措施。此外，AMP 激活蛋白激酶 (AMPK) 的激活有助于调节簇蛋白执行的线粒体动力学。从机制上讲，凝聚素促进 AMPK α 及其下游靶乙酰辅酶 A 羧化酶 (ACC) 的磷酸化，而抑制 AMPK α 则抵消了凝聚素过表达对线粒体动力学的改善。总而言之，这些研究结果表明，簇蛋白通过抑制 AMPK 介导的线粒体断裂，在糖尿病条件下对内皮细胞发挥有益作用。
Clusterin (CLU) is a stress-responding protein associated with cytoprotection in a broad range of pathological processes. However, clusterin's function in diabetes-induced endothelial dysfunction has not been defined. Herein, using two diabetes models, we investigated the role of clusterin in endothelial dysfunction triggered by diabetes and the molecular mechanisms involved. The results revealed that clusterin overexpression inhibited ICAM-1/VCAM-1 expression in aortas and improved endothelium-dependent vasodilatation in db/db diabetic mice and streptozotocin (STZ)-induced diabetes models. Consistently, in vitro, adenoviral clusterin overexpression reduced the expression of a range of pro-inflammatory cytokines and suppressed monocyte adhesion to endothelial cells subjected to high glucose and high palmitate. Further study indicated that clusterin overexpression mitigated mitochondrial excessive fission and reduced mitochondrial ROS production. Conversely, silencing clusterin aggravated mitochondrial fission and endothelial inflammatory activation in high glucose-exposed endothelial cells. Accumulating evidence indicates that impaired mitochondrial dynamics plays a considerable role in promoting endothelial dysfunction in diabetic subjects. Therefore, treatments targeting mitochondrial undue fission may be promising measures to prevent vascular complications of diabetes. Furthermore, AMP-activated protein kinase (AMPK) activation contributed to the modulation of mitochondrial dynamics executed by clusterin. Mechanistically, clusterin promoted the phosphorylation of AMPK alpha and its downstream target acetyl-CoA carboxylase (ACC), while the inhibition of AMPK alpha negated the improvement in mitochondrial dynamics provided by clusterin overexpression. Over all, these findings suggest that clusterin exerts beneficial effects in endothelial cells under diabetic conditions via inhibiting mitochondrial fragmentation mediated by AMPK.