Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the Development of Diabetic Cardiomyopathy

Abstract

The mechanisms for the development of diabetic cardiomyopathy remain largely unknown. Methylglyoxal (MG) can accumulate and promote inflammation and vascular damage in diabetes. We examined if overexpression of the MG-metabolizing enzyme glyoxalase 1 (GLO1) in macrophages and the vasculature could reduce MG-induced inflammation and prevent ventricular dysfunction in diabetes. Hyperglycemia increased circulating inflammatory markers in wild-type (WT) but not in GLO1-overexpressing mice. Endothelial cell number was reduced in WT-diabetic hearts compared with nondiabetic controls, whereas GLO1 overexpression preserved capillary density. Neuregulin production, endothelial nitric oxide synthase dimerization, and Bcl-2 expression in endothelial cells was maintained in the hearts of GLO1-diabetic mice and corresponded to less myocardial cell death compared with the WT-diabetic group. Lower receptor for advanced glycation end products and tumor necrosis factor-α (TNF-α) levels were also observed in GLO1-diabetic versus WT-diabetic mice. Over a period of 8 weeks of hyperglycemia, GLO1 overexpression delayed and limited the loss of cardiac function. In vitro, MG and TNF-α were shown to synergize in promoting endothelial cell death, which was associated with increased angiopoietin 2 expression and reduced Bcl-2 expression. These results suggest that MG in diabetes increases inflammation, leading to endothelial cell loss. This contributes to the development of diabetic cardiomyopathy and identifies MG-induced endothelial inflammation as a target for therapy.

The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart

“…The early stages of diabetic cardiomyopathy are commonly characterised by LV diastolic dysfunction and ventricular hypertrophy, and in later stages by LV systolic dysfunction progressing to decompensated heart failure [3,5]. Consistent with previous studies [14], our data confirm the presence of LV diastolic dysfunction at 16 weeks of age in Akita mice. Evaluation of both Doppler flow and tissue Doppler echocardiography revealed that 16 weeks of hyperglycaemia conferred a reduction in e′/a′ ratio and E/A ratio, and a prolongation of deceleration time (Fig.…”

Cinnamaldehyde protects from methylglyoxal‐induced vascular damage: Effect on nitric oxide and advanced glycation end products

“…Results are expressed as mean ± SE of mean (n = 3). # shows a significant difference (<0.05) when compared to control, *shows a significant difference (<0.05) when compared to MG vascular dysfunction among other complications, such as aging and hypertension (Nigro et al, 2017;Vulesevic et al, 2016). El-Bassossy et al (2016) even went on to argue that MG is responsible for an amplified contractile response similar to that observed in diabetes.…”

“…Such vascular dysfunction is mostly characterized by an amplified vascular contraction which consequently hinders complete vasodilation (Bahia et al, ). The use of MG to study such vascular complications is justified by recent studies claiming that MG accumulation in the body is associated with vascular dysfunction among other complications, such as aging and hypertension (Nigro et al, ; Vulesevic et al, ). El‐Bassossy et al () even went on to argue that MG is responsible for an amplified contractile response similar to that observed in diabetes.…”

Deoxyactein protects pancreatic β-cells against methylglyoxal-induced oxidative cell damage by the upregulation of mitochondrial biogenesis

“…Deoxyactein decreases the production of IL-1β in MG-exposed RIN-m5F cells. MG promotes the formation of pro-inflam- matory cytokines in various cell types (26)(27)(28). Thus, we also investigated whether deoxyactein modulates the production of IL-1β in MG-exposed cells (Fig.…”