Glyoxal induces arterial injury through the inactivation of receptors and signaling pathways

Glyoxal exposure is associated with a spectrum of adverse health outcomes, including arterial injury. While existing evidence confirms that glyoxal targets oxidative stress and the mitogen-activated protein kinase pathway, the precise underlying mechanism of glyoxal-induced arterial damage remains elusive. In this study, we aimed to elucidate the molecular mechanism driving glyoxal-induced arterial injury through a combination of in vitro and in vivo experiments. In vitro, we treated human aortic endothelial cells with glyoxal, then performed cell viability assays, tandem mass tag (TMT)-based quantitative proteomics, parallel reaction monitoring (PRM), glutathione quantification for oxidative stress assessment, western blotting, and quantitative polymerase chain reaction (qPCR) analysis. In vivo, we administered glyoxal to C57BL/6 mice, after which we conducted biochemical, histological, and immunohistochemical assays to evaluate arterial pathological changes. In vitro, the proteomic profiling results were further validated via PRM and western blotting, which confirmed that glyoxal exposure induces energy metabolism dysfunction, aberrant vascular endothelial growth factor receptor (VEGF-R) expression, and signaling pathway inactivation. Consistent with the proteomic results, we detected reduced protein levels of VEGF-R (36.4% reduction), insulin-like growth factor receptor (IGF-R, 21.6% reduction ), and insulin receptor (INS-R, 16.4% reduction) relative to control after glyoxal treatment. Compared to the control group, the glyoxal-exposed group exhibited a 48.7% reduction in the phosphorylation levels of ErbB2 and ErbB4, while total protein levels of ErbB2 and ErbB4 (106.0% of the control level) were comparable between the two groups. In addition, the levels of Wnt signaling-related proteins—including β-catenin (52.5% of the control level) and Wnt ligands—were significantly decreased following glyoxal treatment, relative to the control. Consistent with our in vitro results, we observed that the protein levels of VEGF-R (47.7% reduction), β-catenin (25.7% reduction), and INS-R (66.0% reduction) were decreased relative to the control group after in vivo glyoxal treatment. Collectively, our findings outline a comprehensive molecular portrait of glyoxal-induced arterial injury, which provides a foundational framework that may advance the development of precision medicine strategies for glyoxal-related vascular disease. Our previous study demonstrated that oxidative stress and MAPK pathways are important targets of glyoxal (GX); however, the specific mechanism is not completely understood at present. Therefore, this study investigates the AI mechanism induced by GX based on the proteomics. These novel mechanisms include INS-R, IGF-R, and VEGF-R damage and systematic changes in the Wnt and ErbB signaling pathways. These injuries correspond to abnormal energy metabolism and function of HAECs, causing aberrant vascular function, inflammation, and abnormal vascular structure.