Luisa Wensky1,2, Soroush Mohammadi Jouabadi3, Sabrina Ribeiro Gonsalez4, Jean L.J.M. Scheijen1,2, Marjo van de Waarenburg1,2, Anton J.M. Roks3, Casper Schalkwijk1,2, Philippe Vangrieken1,2,5.
1Department of Internal Medicine, Maastricht University, Maastricht, Netherlands; 2Cardiovascular Research Institute Maastricht (CARIM); 3Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands; 4Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil; 5Department of Pharmacology and Toxicology, Maastricht University.
luisa.wensky@maastrichtuniversity.nl
Chronic hyperglycemia in diabetes promotes cardiovascular complications, partly through accumulation of methylglyoxal (MGO), a reactive glycolytic byproduct that contributes to the formation of advanced glycation endproducts and induces endothelial dysfunction. This study investigates whether lowering endogenous MGO can improve vascular function in a type 1 diabetes mouse model.
Eight-week-old Tie2Cre mice (n=16/group) were injected intraperitoneally with streptozotocin (50mg/kg) or citrate buffer (vehicle) for five consecutive days to induce diabetes. From 10 weeks of age, mice received either an MGO-lowering cocktail (2 g/L pyridoxamine, 0.125 g/L hesperidin, 0.1 g/L resveratrol) or vehicle in drinking water. Echocardiography was performed one week prior to sacrifice at 20 weeks of age. Vascular function of the thoracic aorta was assessed through wire myography, and plasma and urine samples were analysed for multiple biomarkers.
Diabetes impaired acetylcholine-induced vasorelaxation compared to controls (maximal response: -29.9±4.4% vs. -69.6±3.6%, p<0.001), whereas cocktail treatment significantly improved endothelial function in the diabetic mice (-53.6±7.6%, p=0.008). Plasma MGO levels were significantly higher in diabetic mice than in non-diabetic controls (1700.4±336.0 nmol/L vs. 1042.3±79.0 nmol/L, p=0.005), and the cocktail treatment showed a trend toward mitigating this increase (1147.1±75.3 nmol/L, p=0.06). Plasma levels of E-selectin (67.0±3.3 ng/mL vs. 45.5±2.2 ng/mL, p<0.001) and intercellular adhesion molecule 1 (ICAM-1; 456.7± 45.8 ng/mL vs. 292.9±9.0 ng/mL, p<0.001) were elevated in diabetic mice compared to controls, and cocktail treatment significantly reduced ICAM-1 levels (344.9±14.9 ng/mL, p=0.005).
Treatment with the MGO-lowering cocktail reduced plasma MGO levels, significantly restored endothelial function, and attenuated vascular inflammation in diabetic mice. These findings support targeting MGO as a promising therapeutic strategy to improve vascular function and to mitigate diabetes-related cardiovascular complications.