College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-Gu, Incheon, 21936, Republic of Korea.
Korea Food Research Institute, 245, Nongsaengmyeong-Ro, Iseo-Myeon, Wanju_Gun, Jeollabuk-Do, 55365, Republic of Korea.
Cell Death Dis. 2020 May 28;11(5):403. doi: 10.1038/s41419-020-2602-1.
Methylglyoxal (MGO)-induced cellular apoptosis, oxidative stress, inflammation, and AGE formation are specific events that induce vascular endothelial cell (EC) toxicity in endothelial dysfunction (ED). MGO accumulates quickly in various tissues and plays a prominent role in the pathogeneses of several diabetic complications. Unbalanced angiogenesis is a gateway to the development of diabetic complications. EC apoptosis and autophagy work together to regulate angiogenesis by interacting with different angiogenic factors. In addition to understanding the deep mechanism regarding MGO-dependent autophagy/apoptosis may provide new therapeutic applications to treat diabetes and diabetic complications. Therefore, the present study aimed to investigate the regulatory effects of MGO-induced autophagy and apoptosis on angiogenesis in HAoEC and to elucidate the molecular mechanisms to discover new target base therapy for diabetes and diabetic complications. In MGO-stimulated HAoEC, protein expression was identified using a western blot, autophagosomes were observed by bio-transmission electron microscopy (TEM), and cell autophagic vacuoles and flux were measured using a confocal microscope. We found that MGO significantly induced autophagy, declined the pro-angiogenic effect, decreased proliferation, migration, and formation of tube-like structures, and increased autophagic vacuoles, flux and autophagosomes in the HAoEC in a dose-dependent manner. We observed that MGO-induced autophagic cell death and inhibited the ROS-mediated Akt/mTOR signaling pathway. MGO also triggered apoptosis by elevating the cleaved caspase-3 to Bax/Bcl-2 ratio and through activation of the ROS-mediated MAPKs (p-JNK, p-p38, and p-ERK) signaling pathway. Collectively, these findings suggest that autophagy and apoptosis inhibit angiogenesis via the ROS-mediated Akt/mTOR and MAPKs signaling pathways, respectively, when HAoEC are treated with MGO.
甲基乙二醛（MGO）诱导的细胞凋亡、氧化应激、炎症和 AGE 形成是诱导血管内皮细胞（EC）毒性的特定事件，导致内皮功能障碍（ED）。MGO 在各种组织中迅速积累，在几种糖尿病并发症的发病机制中起重要作用。不平衡的血管生成是糖尿病并发症发展的门户。EC 凋亡和自噬通过与不同的血管生成因子相互作用共同调节血管生成。除了了解 MGO 依赖性自噬/凋亡的深层机制外，还可能为治疗糖尿病和糖尿病并发症提供新的治疗应用。因此，本研究旨在探讨 MGO 诱导的自噬和凋亡对 HAoEC 血管生成的调节作用，并阐明分子机制，以发现糖尿病和糖尿病并发症的新靶基治疗。在 MGO 刺激的 HAoEC 中，使用 Western blot 鉴定蛋白表达，使用生物透射电子显微镜（TEM）观察自噬体，使用共聚焦显微镜测量细胞自噬空泡和通量。我们发现，MGO 显著诱导自噬，降低促血管生成作用，降低增殖、迁移和管状结构形成，并且以剂量依赖性方式增加 HAoEC 中的自噬空泡、通量和自噬体。我们观察到 MGO 诱导自噬细胞死亡并抑制 ROS 介导的 Akt/mTOR 信号通路。MGO 还通过增加 cleaved caspase-3 与 Bax/Bcl-2 比值以及激活 ROS 介导的 MAPKs（p-JNK、p-p38 和 p-ERK）信号通路来触发凋亡。总之，这些发现表明，当 HAoEC 受到 MGO 处理时，自噬和凋亡通过 ROS 介导的 Akt/mTOR 和 MAPKs 信号通路分别抑制血管生成。
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