Circulation research
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Circulation research · Oct 2005
Activation of the sphingosine kinase-signaling pathway by high glucose mediates the proinflammatory phenotype of endothelial cells.
Vascular endothelial cells are key targets for hyperglycemic damage that facilitates vascular inflammation and the vasculopathy associated with diabetes mellitus. However, the mechanisms underlying this damage remain undefined. We now demonstrate that hyperglycemia induces activation of sphingosine kinase (SphK), which represents a novel signaling pathway that mediates endothelial damage under ambient high glucose conditions. ⋯ In addition, an increase in SphK1 phosphorylation was detected in a protein kinase C- and extracellular signal-regulated kinase 1/2-dependent manner, which accounts for the high glucose-induced increases in SphK activity. Importantly, inhibition of SphK1 by either a chemical inhibitor (N',N'-dimethylsphingosine) or expression of a dominant-negative mutant of SphK1 (SphK(G82D)), or SphK1-specific small interfering RNA, strongly protected endothelial cells against high glucose-induced damage, as characterized by an attenuation in the expression of proinflammatory adhesion molecules, adhesion of leukocytes to endothelial cells, and nuclear factor kappaB activation. Thus, interventions that target the SphK-signaling pathway may have the potential to prevent vascular lesions under hyperglycemic conditions.