Methylglyoxal Induces Apoptosis Mediated by Reactive Oxygen Species in Bovine Retinal Pericytes

Abstract

One of the histopathologic hallmarks of early diabetic retinopathy is the loss of pericytes. Evidences suggest that the pericyte loss in vivo is mediated by apoptosis. However, the underlying cause of pericyte apoptosis is not fully understood. This study investigated the influence of methylglyoxal (MGO), a reactive α-dicarbonyl compound of glucose metabolism, on apoptotic cell death in bovine retinal pericytes. Analysis of internucleosomal DNA fragmentation by ELISA showed that MGO (200 to 800 µM) induced apoptosis in a concentration-dependent manner. Intracellular reactive oxygen species were generated earlier and the antioxidant, N-acetyl cysteine, inhibited the MGO-induced apoptosis. NF-κB activation and increased caspase-3 activity were detected. Apoptosis was also inhibited by the caspase-3 inhibitor, Z-DEVD-fmk, or the NF-κB inhibitor, pyrrolidine dithiocarbamate. These data suggest that elevated MGO levels observed in diabetes may cause apoptosis in bovine retinal pericytes through an oxidative stress mechanism and suggests that the nuclear activation of NF-κB are involved in the apoptotic process.

Glyoxalase I Is Critical for Human Retinal Capillary Pericyte Survival under Hyperglycemic Conditions

“…This MGO concentration is less than that previously reported to cause retinal pericyte apoptosis (22). Fig.…”

“…Kim et al (22) report that MGO-mediated apoptosis in retinal pericytes may occur via an oxidative stress mechanism involving NF-B (22). Du et al (47,48) likewise suggest a role for oxidative stress generated by incubation of Jurkat cells with MGO, which then triggers c-Jun NH 2 -terminal kinase activation and subsequent apoptosis.…”

“…Apoptosis prompted by this mechanism is probably due to enhanced oxidative stress within the cells. In fact, antioxidants inhibit apoptosis caused by MGO and AGEs (22,23). We showed that extracellular matrix proteins modified by dicarbonyls induce pericytes apoptosis as well (24).…”

“…MGO 2 is an ␣-oxoaldehyde that is highly reactive with lysine or arginine residues in proteins, modifying them at their amine moieties to form AGEs (17,18). Elevated levels of both MGO and AGEs have been observed in serum and various tissues of diabetic patients, respectively (19,20), and both AGEs and MGO cause pericyte apoptosis (21,22). Apoptosis prompted by this mechanism is probably due to enhanced oxidative stress within the cells.…”

Glycolaldehyde Induces Cytotoxicity and Increases Glutathione and Multidrug-Resistance-Associated Protein Levels in Schwann Cells

“…For example, methylglyoxal increases ROS production in mouse Schwann cells, bovine retinal pericytes, and human aortic endothelial cells. [12][13][14] Intracellular glutathione (GSH) is depleted in Schwann cells incubated with methylglyoxal.…”