Protective Effects of the Sodium/Calcium Exchanger Inhibitor on Endothelial Dysfunction Induced by High Glucose

Abstract

This study was designed to investigate the protective effects of KB-R7943, an inhibitor of sodium/calcium exchanger (NCX) on endothelial dysfunction induced by high glucose in endothelial cells. NCX expression, NCX activity and oxidative stress index were determined after endothelial cells were exposed to high glucose in the absence and presence of KB-R7943. Coincubation of endothelial cells with high glucose for 6, 12, 24 and 48 h resulted in a significant decrease in NCX expression, superoxide dismutase (SOD) activity and the release of nitric oxide (NO), and increased NCX activity and malondialdehyde (MDA) production. These effects were abolished by KB-R7943. A similar effect was observed after treatment of endothelial cells with H-7, a protein kinase C (PKC) inhibitor and NADPH oxidase inhibitor (DPI). These results suggest that the sodium/calcium exchanger inhibitor exerts beneficial effects on high glucose-induced endothelial dysfunction, which may be related to PKC signal pathway.

Ginsenoside Rg-1 prevents elevated cytosolic Ca2+ via store-operated Ca2+ entry in high-glucose–stimulated vascular endothelial and smooth muscle cells

“…Exposure to abnormally high glucose concentrations has been reported to increase NCX activity and contribute to diabetic microvascular complications [ 26 , 27 ]. This increase in NCX activity was inhibited by KB-R7943, suggesting that hyperglycemia-induced NCX activity is strongly associated with the NCX reverse mode [ 28 ]. In the present study, Rg-1 treatment inhibited the abnormally increased SOCE induced by high glucose concentrations, suggesting that Rg-1 may inhibit Ca 2+ influx through the NCX reverse mode.…”

“…In line with these reports, catalase treatment of platelets from patients with type 2 diabetes mellitus increased the PMCA tyrosine phosphorylation induced by thapsigargin plus ionomycin, suggesting that oxidative stress is involved in the reduced platelet PMCA activity seen in diabetic patients [ 34 ]. High glucose also significantly increased NCX activity and malondialdehyde production in human umbilical vascular endothelial cells, and this effect was abolished by KB-R7943-mediated inhibition of the reverse mode of NCX, indicating that increased reverse-mode NCX activity plays an important role in high glucose-induced endothelial dysfunction [ 28 ]. Rg-1 has demonstrated several pharmacological actions including antioxidant effects [ 35 ].…”

Na+/Ca2+ Exchanger Inhibitor Restores Endothelium-dependent Relaxation in Diabetic Rat Aorta

“…Therefore, detailed investigations conducted in experimental diabetic models may provide clues to the mechanism of this dysfunction. Previous work from our laboratory suggests that KB-R7943 (an inhibitor of Na + /Ca 2 + exchanger) can restore impaired EDR induced by high glucose (or advanced glycosylation end products) in isolated rat aorta and exerted its beneficial effect by both inhibiting adhesion of monocytes to endothelial cells and the expression of intercellular adhesion molecule-1 in endothelial cells (Su et al, 2008;Li et al, 2010;Liu et al, 2015). However, there are no reports as to whether Na + /Ca 2 + exchanger inhibitor is able to protect against the impairment of endothelial functions in diabetic rat aorta.…”