Dysfunctional signaling pathway for nitric oxide production in endothelial cells chronically exposed to high glucose or high fatty acids

Abstract

Overwhelming evidence indicates that endothelial cell dysfunction in diabetes is characterized by diminished endothelium-dependent relaxation, but the underlying molecular mechanism remains inconclusive. Hyperglycemia and hyperlipidemia are the two possible causes for the endothelial cell dysfunction. Therefore, the effects of high glucose and high fatty acids on NO production and possible alterations of signaling pathways implicated in this scenario were studied. Results showed that exposure of large vascular endothelial cells to high glucose or high fatty acids for 5 or 10 days significantly reduced agonists stimulated NO production in both time- and dose-dependent manner. The diminished NO formation was probably due to attenuation in agonist-induced elevations of intracellular free Ca2+ levels under these conditions. Both agonist-promoted intracellular Ca2+ mobilization and extracellular Ca2+ entry were affected. In addition, bradykinin-evoked formation of Ins(1,4,5)P3 was also deceased following high glucose culture. This abnormality might be due to a reduction of the number or the affinity of receptors in high glucose and high fatty acids cultured endothelial cells, respectively. This defect in NO signaling pathway may be the result of excessive activation of protein kinase C and formation of oxidants.