Hyperglycaemia is a hallmark of diabetes and has been found to activate a reactive oxygen species (ROS)-generating enzyme, NADPH oxidase 2 (Nox2), which is involved in inflammation and diabetic cardiovascular complications. G-protein coupled receptor 43 (GPCR43) has been reported recently to be expressed in various tissues; however, its role in the human vascular system remains unknown. Acetate is agonist of GPCR43. In this study we investigated the expression and redox-signalling pathway of GPCR43 in human saphenous vein sections in a cultured model of high glucose-induced Nox2 activation and vessel dysfunction. Vessels were cultured in normal (5 mM, control) or high glucose (30 mM) medium for 24 hours in the presence or absence of acetate (5 mM) to activate GPCR43. The morphological and structural integrities of the vessels were confirmed by histological examination (H & E staining). GPCR43 was detected throughout the entire vessel wall including the endothelium, smooth muscles and adventitia. Compared to control vessels, high glucose increased (33%±10%) the expression of Nox2 in the endothelium as evaluated using immunofluorescence quantification. Increased Nox2 expression was accompanied by increased ROS production, as detected by NADPH-dependent lucigenin-chemiluminescence, and an increase in the phosphorylation of redox-sensitive signalling pathways i.e. ERK1/2 (77%±18%) and JNK (99%±23%). Acetate has no significant effect on GPCR43 expression, but prevented significantly the high glucose-induced Nox2 activation and ERK1/2 and JNK phosphorylation. In conclusion, GPCR43 is highly expressed in human vasculature and may have a therapeutic potential to reduce high glucose-induced Nox2 activation and oxidative damage of vascular function in diabetes.
- CARDIAC PROCEDURES AND THERAPY
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