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Analyzing the Permeability of the Blood-Brain Barrier by Microbial Traversal through Microvascular Endothelial Cells
Published on: February 14, 2020
Molecular mechanisms of methylglyoxal-induced aortic endothelial dysfunction in human vascular endothelial cells
Jae Hyuk Lee1, Amna Parveen1, Moon Ho Do1,2
1College of Pharmacy, Gachon University, #191, Hambakmoero, Yeonsu-Gu, Incheon, 21936, Republic of Korea.
Abstract:
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.
Insights
Methylglyoxal (MGO) triggers cell death pathways, including autophagy and apoptosis, in human aortic endothelial cells (HAoECs). These processes inhibit blood vessel formation (angiogenesis) by disrupting key signaling pathways, offering potential therapeutic targets for diabetic complications.
Area of Science:
- Endocrinology
- Cell Biology
- Molecular Biology
Background:
- Methylglyoxal (MGO) is a reactive dicarbonyl compound implicated in diabetic complications.
- Endothelial dysfunction (ED) involves cellular apoptosis, oxidative stress, and inflammation, contributing to diabetic pathologies.
- Unbalanced angiogenesis is a critical factor in the development of diabetic complications, with endothelial cell (EC) apoptosis and autophagy playing regulatory roles.
Purpose of the Study:
- To investigate the regulatory effects of MGO-induced autophagy and apoptosis on angiogenesis in human aortic endothelial cells (HAoECs).
- To elucidate the molecular mechanisms underlying MGO's impact on angiogenesis.
- To identify potential therapeutic targets for diabetes and its complications.
Main Methods:
- Protein expression analysis via western blot.
- Observation of autophagosomes using bio-transmission electron microscopy (TEM).
- Measurement of autophagic vacuoles and flux using confocal microscopy in MGO-stimulated HAoECs.
Main Results:
- MGO significantly induced autophagy and apoptosis in HAoECs in a dose-dependent manner.
- MGO decreased the pro-angiogenic effect, proliferation, migration, and tube-like structure formation.
- MGO inhibited the ROS-mediated Akt/mTOR signaling pathway and activated ROS-mediated MAPKs signaling pathway, leading to autophagic cell death and apoptosis.
Conclusions:
- Autophagy and apoptosis induced by MGO inhibit angiogenesis in HAoECs.
- These processes are mediated via the ROS-mediated Akt/mTOR and MAPKs signaling pathways, respectively.
- Understanding these mechanisms may lead to new therapeutic strategies for diabetes and diabetic complications.
