Abstract
AIMS: Diabetes is a leading cause of mortality worldwide, primarily due to cardiovascular diseases (CVD). Arterial stiffness is a CVD predictor and is associated with increased mortality in diabetic individuals. In diabetes, the formation and accumulation of methylglyoxal (MGO), a highly reactive glycolysis by product and a major precursor in advanced glycation endproducts (AGEs) formation, has been implicated in CVD. In this study, we investigated the role of endogenous MGO in arterial stiffening in a mouse model of type 1 diabetes (T1D) overexpressing the MGO-detoxifying enzyme glyoxalase-1 (GLO1). METHODS AND RESULTS: Diabetes was induced in C57BL/6 J mice through 5-day streptozotocin injections. 17-week-old control, diabetic, and GLO1-overexpressing diabetic mice were used. Fasting glucose in diabetes and GLO1/diabetes was higher than control. Plasma, urine, and aortic MGO, AGEs, and cross-links were determined using ultra-performance liquid chromatography tandem mass spectrophotometry. MGO was increased in plasma and urine in diabetic mice, while GLO1 decreased MGO in urine. The AGE cross-link pentosidine in aorta was increased in diabetes and ameliorated by GLO1. Tail-cuff blood pressure and carotid-femoral pulse wave velocity were measured preceding euthanasia, and did not differ between groups. Descending thoracic aorta ex vivo passive biaxial arterial wall biomechanics were measured and diabetes showed elevated ex vivo PWV, which was attenuated by GLO1 overexpression. Material viscoelasticity was decreased in diabetes and normalised by GLO1 overexpression. Second harmonic generation imaging demonstrated a predominant axial orientation of diabetic collagen fibres, while GLO1/diabetes led to a uniform orientation. When comparing GLO1/diabetes and diabetes, bulk RNA sequencing revealed 137 differentially expressed genes affecting extracellular matrix organisation, cell-cell and cell-matrix communication and interaction pathways. CONCLUSION: In an animal model of T1D, GLO1 overexpression attenuates arterial stiffening at the underlying material levels, by modifying collagen ultrastructure and viscoelastic properties. Targeting MGO may provide a novel approach to prevent arterial T1D stiffening.