Pencheva Margarita G, Berends Eline, van der Laan Koen W F, Giudici Alessandro, Niessen Petra, Scheijen Jean L J M, Vangrieken Philippe, Leenders Peter, Delhaas Tammo, Caiment Florian, Kutmon Martina, Trujillo Fabiola M, Wouters Kristiaan, Foulquier Sébastien, Spronck Bart, Reesink Koen D, Schalkwijk Casper G
Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Universiteitssingel 50, 6229ER, Maastricht, The Netherlands.
Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
Cardiovasc Diabetol. 2025 Jul 11;24(1):283. doi: 10.1186/s12933-025-02823-4.
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).
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.
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.
糖尿病是全球主要的死亡原因，主要归因于心血管疾病（CVD）。动脉僵硬度是心血管疾病的一个预测指标，并且与糖尿病患者死亡率增加相关。在糖尿病中，甲基乙二醛（MGO）的形成和积累，一种高反应性糖酵解副产物和晚期糖基化终产物（AGEs）形成的主要前体，被认为与心血管疾病有关。在本研究中，我们在过表达MGO解毒酶乙二醛酶-1（GLO1）的1型糖尿病（T1D）小鼠模型中研究了内源性MGO在动脉僵硬中的作用。
通过5天注射链脲佐菌素在C57BL/6 J小鼠中诱导糖尿病。使用17周龄的对照、糖尿病和过表达GLO1的糖尿病小鼠。糖尿病组和GLO1/糖尿病组的空腹血糖高于对照组。使用超高效液相色谱串联质谱法测定血浆、尿液和主动脉中的MGO、AGEs和交联物。糖尿病小鼠血浆和尿液中的MGO增加，而GLO1降低尿液中的MGO。糖尿病组主动脉中的AGE交联物戊糖苷增加，而GLO1可改善这种情况。在安乐死之前测量尾套血压和颈股脉搏波速度，各组之间没有差异。测量离体降主动脉被动双轴动脉壁生物力学，糖尿病组显示离体脉搏波速度升高，而过表达GLO1可使其减弱。糖尿病组材料粘弹性降低，而过表达GLO1可使其恢复正常。二次谐波成像显示糖尿病胶原纤维主要呈轴向排列，而GLO1/糖尿病组则呈均匀排列。当比较GLO1/糖尿病组和糖尿病组时，大量RNA测序揭示了137个差异表达基因，这些基因影响细胞外基质组织、细胞-细胞和细胞-基质通讯及相互作用途径。
在T1D动物模型中，过表达GLO1通过改变胶原超微结构和粘弹性特性，在基础材料水平上减轻动脉僵硬。靶向MGO可能为预防T1D动脉僵硬提供一种新方法。
