Methylglyoxal Potentiates Palmitic Acid-Induced Endothelial Dysfunction and Atherogenesis in HUVECs

Abstract Endothelial dysfunction is a key pathological mechanism in atherosclerotic cardiovascular disease, and methylglyoxal (MGO) has been identified as a major contributor to endothelial cell damage through its overabundance. In this study, the effects of MGO on atherosclerotic human endothelial cells were investigated. HUVECs were pre-treated with 1 mM PA for 24 h and then co-treated with 60 or 400 µM MGO for an additional 24 h. They measured intracellular lipid accumulation by Oil-Red O staining, apoptotic changes and nitrosative stress using flow cytometry and the Griess assay, and gene expression patterns associated with angiogenesis, inflammation, lipoprotein, and cholesterol metabolism by real-time PCR. Results showed that MGO treatment did not alter lipid droplet distribution in PA-treated HUVECs but significantly decreased apoptosis by 0.7% and 0.31% at 60 and 400 µM, respectively. MGO at a low dose (60 µM) enhanced nitric oxide by approximately 0.09%. Gene expression analysis confirmed 2-3-fold increases in LPL, LPA, IL-8, and IFN-γ expression post MGO exposure, whereas IL-6 was elevated only in the combined PA-MGO treatment. The PA-MGO combination significantly altered the expression of angiogenesis-related genes. These results suggest that MGO potentiates inflammation and nitrosative stress in PA-treated endothelial cells via synergistic mechanisms. This increased lipoprotein activity indicates that MGO is implicated in lipid metabolic disturbances and vascular lipotoxicity and offers compelling evidence that MGO contributes to atherosclerosis pathogenesis via metabolic dysregulation and inflammatory gene expression modulation.