Molecular mechanisms of methylglyoxal-induced aortic endothelial dysfunction in human vascular endothelial cells

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.