Melatonin protects endothelial progenitor cells against AGE-induced apoptosis via autophagy flux stimulation and promotes wound healing in diabetic mice.
Melatonin protects endothelial progenitor cells against AGE-induced apoptosis via autophagy flux stimulation and promotes wound healing in diabetic mice.
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DOI：
10.1038/s12276-018-0177-z
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发表时间：
2018-11-21
影响因子：
12.8
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Jin H;Zhang Z;Wang C;Tang Q;Wang J;Bai X;Wang Q;Nisar M;Tian N;Wang Q;Mao C;Zhang X;Wang X
糖尿病患者伤口愈合延迟。增加的细胞凋亡和内皮祖细胞（EPC）功能障碍与糖尿病伤口愈合延迟有关。褪黑激素是松果体的主要分泌产物，可促进糖尿病伤口愈合，但其作用机制尚不清楚。在这里，EPCs从小鼠骨髓中分离。褪黑素治疗EPCs可减轻晚期糖基化终产物（AGE）诱导的细胞凋亡和细胞功能障碍。我们进一步研究了褪黑激素处理后的自噬通量，发现AGE处理的EPCs中轻链3（LC 3）和p62蛋白水平增加。然而，溶酶体相关膜蛋白2的表达下降，表明自噬通量受损的EPCs与AGEs治疗。然后，我们评估了褪黑激素治疗后的自噬通量，发现褪黑激素增加了LC 3水平，但减弱了p62的积累，这表明褪黑激素对自噬通量的刺激作用。阻断自噬流的氯喹部分取消褪黑激素的保护作用，表明自噬流参与褪黑激素的保护作用。此外，我们发现AMPK/mTOR信号通路参与褪黑素刺激的自噬通量。一项体内研究还表明，褪黑激素治疗改善了链脲佐菌素诱导的糖尿病伤口愈合模型中受损的伤口愈合。因此，我们的研究表明，褪黑激素通过自噬通量刺激保护EPCs免于凋亡和功能障碍，并改善体内受损的伤口愈合，从而深入了解其在糖尿病伤口愈合中的作用机制。褪黑激素是一种睡眠调节激素，通过保护血液中的伤口愈合细胞，即内皮祖细胞（EPCs），可以加速糖尿病患者的伤口愈合。在糖尿病中，EPCs受损，失去迁移到伤口和形成新组织的能力，并过早死亡。延迟愈合可能导致溃疡，感染，有时截肢。最近有报道称褪黑激素可以促进伤口愈合，但其机制尚不清楚。中国温州医科大学的Xiangyang Wang和Xiaolei Zhang及其同事假设褪黑激素可能保护EPCs免受糖尿病诱导的损伤。他们发现褪黑激素提高了EPCs消除受损成分的能力，使它们能够自我修复并恢复其伤口愈合功能。在进一步的实验中，用褪黑激素治疗的糖尿病小鼠比未治疗的小鼠愈合得更快。这些结果可能有助于改善糖尿病并发症的治疗。
Wound healing is delayed in diabetic patients. Increased apoptosis and endothelial progenitor cell (EPC) dysfunction are implicated in delayed diabetic wound healing. Melatonin, a major secretory product of the pineal gland, promotes diabetic wound healing; however, its mechanism of action remains unclear. Here, EPCs were isolated from the bone marrow of mice. Treatment of EPCs with melatonin alleviated advanced glycation end product (AGE)-induced apoptosis and cellular dysfunction. We further examined autophagy flux after melatonin treatment and found increased light chain 3 (LC3) and p62 protein levels in AGE-treated EPCs. However, lysosome-associated membrane protein 2 expression was decreased, indicating that autophagy flux was impaired in EPCs treated with AGEs. We then evaluated autophagy flux after melatonin treatment and found that melatonin increased the LC3 levels, but attenuated the accumulation of p62, suggesting a stimulatory effect of melatonin on autophagy flux. Blockage of autophagy flux by chloroquine partially abolished the protective effects of melatonin, indicating that autophagy flux is involved in the protective effects of melatonin. Furthermore, we found that the AMPK/mTOR signaling pathway is involved in autophagy flux stimulation by melatonin. An in vivo study also illustrated that melatonin treatment ameliorated impaired wound healing in a streptozotocin-induced diabetic wound healing model. Thus, our study shows that melatonin protects EPCs against apoptosis and dysfunction via autophagy flux stimulation and ameliorates impaired wound healing in vivo, providing insight into its mechanism of action in diabetic wound healing. Melatonin, a sleep-regulating hormone, may speed wound healing in patients with diabetes by protecting blood-borne wound-healing cells known as endothelial progenitor cells (EPCs). In diabetes, EPCs become damaged, lose their capacity to migrate to wounds and form new tissue, and die prematurely. Delayed healing can lead to ulcers, infection, and sometimes amputation. Melatonin has recently been reported to promote wound healing, but the mechanism remains unclear. Xiangyang Wang and Xiaolei Zhang at Wenzhou Medical University, China, and coworkers hypothesized that melatonin might protect EPCs from diabetes-induced damage. They found that melatonin improved EPCs’ ability to eliminate damaged components, allowing them to repair themselves and restoring their wound-healing function. In further experiments, diabetic mice treated with melatonin healed faster than untreated mice. These results may help improve treatments for complications of diabetes.
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