NADPH oxidase 2 (Nox2)-derived oxidative stress and redox-signalling have been found to play an important role in hyperglycaemia-induced endothelial dysfunction in diabetes. Acetate (NaA) is a member of the short chain fatty acids (SCFA) family which acts through G-protein coupled receptor 43 (GPCR43) to exert anti-inflammatory effects and to increase insulin sensitivity. However, its action in endothelial cells remains unknown. In this study we investigated the effects of NaA and GPCR43 on high glucose (30 mM, 24 h)-induced Nox2 activation and endothelial cell cycle progression using human pulmonary microvascular endothelial cells (HPMECs). Compared to control cells, high glucose increased significantly i) Nox2-derived superoxide production (48.5±12.6%) as detected by both lucigenin (5 µM)-chemiluminescence and DHE fluorescence; ii) expression of cyclin D, A and E and cell cycle progression from G0/G1 to S and G2/M phases and iii) cell apoptosis (30.66±8.3%) (all p<0.05). These high-glucose induced changes were accompanied by increased Nox2 expression and the activation of stress signalling pathways such as ERK1/2 and NF-κβ. However in the presence of NaA, high glucose-induced endothelial oxidative stress was inhibited significantly and endothelial function was well preserved. We also found that human endothelial cells express GPCR43 receptor and NaA increased the expression of GPCR43. In conclusion, Nox2-derived oxidative stress and redox signalling play a key role in mediating high glucose-induced damage of endothelial cell cycle progression and cell death. NaA through its receptor, GPCR43, inhibits high glucose-induced Nox2 activation, oxidative stress and Nox2 signalling through ERK1/2 and its down-stream pathways.
- CARDIAC PROCEDURES AND THERAPY
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