Department of Rheumatology and Immunology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi`an, Shaanxi, China.
Department of Cardiovascular Surgery, Fuwai Hospital Chinese Academy of Medical Sciences, ShenZhen, China.
J Steroid Biochem Mol Biol. 2021 Sep;212:105948. doi: 10.1016/j.jsbmb.2021.105948. Epub 2021 Jul 2.
Oxidative stress injury is an important link in the pathogenesis of diabetes, and reducing oxidative stress damage caused by long-term hyperglycemia is an important diabetic treatment strategy. Melatonin has been proved to be a free radical scavenger with strong antioxidant activity, and its protective effect on diabetes and the complications has been confirmed. However, the role and potential mechanism of melatonin in oxidative stress injury of diabetic aorta have not been reported. Besides, Notch signaling pathway plays an important role in vascular growth, differentiation, and apoptosis. We speculated that melatonin could improve oxidative stress injury of diabetic aorta through Notch1/Hes1 signaling pathway. STZ-induced diabetic rats and vascular smooth muscle cells (VSMCs) cultured with high glucose were treated with or without melatonin, melatonin receptor antagonist Luzindole, γ-secretase inhibitor DAPT respectively. We found that melatonin could improve the oxidative stress injury of diabetic aorta and reduce the apoptosis of VSMCs. Interestingly, melatonin could activate Notch1 signaling pathway, play an antioxidant role, and reduce the expression of apoptosis-related proteins. However, these protective effects could be largely eliminated by Luzindole or DAPT. We concluded that the repression of Notch1 signaling pathway would inhibit the repair of oxidative stress injury in diabetes. Melatonin could ameliorate oxidative stress injury and apoptosis of diabetic aorta by activating Notch1/Hes1 signaling pathway.
氧化应激损伤是糖尿病发病机制中的一个重要环节，减少长期高血糖引起的氧化应激损伤是糖尿病治疗的重要策略。褪黑素已被证明是一种具有强抗氧化活性的自由基清除剂，其对糖尿病及其并发症的保护作用已得到证实。然而，褪黑素在糖尿病主动脉氧化应激损伤中的作用及其潜在机制尚未报道。此外，Notch 信号通路在血管生长、分化和凋亡中发挥重要作用。我们推测，褪黑素可能通过 Notch1/Hes1 信号通路改善糖尿病主动脉的氧化应激损伤。用 STZ 诱导的糖尿病大鼠和高糖培养的血管平滑肌细胞（VSMCs）分别用或不用褪黑素、褪黑素受体拮抗剂 Luzindole、γ-分泌酶抑制剂 DAPT 处理。我们发现，褪黑素可以改善糖尿病主动脉的氧化应激损伤，减少 VSMCs 的凋亡。有趣的是，褪黑素可以激活 Notch1 信号通路，发挥抗氧化作用，降低凋亡相关蛋白的表达。然而，这些保护作用可以通过 Luzindole 或 DAPT 大大消除。我们得出结论，Notch1 信号通路的抑制会抑制糖尿病中氧化应激损伤的修复。褪黑素可以通过激活 Notch1/Hes1 信号通路改善糖尿病主动脉的氧化应激损伤和细胞凋亡。
