Activation of sphingosine kinase-1 mediates induction of endothelial cell proliferation and angiogenesis by epoxyeicosatrienoic acids

Cardiovascular Research
Guijun YanJianxin Sun

Abstract

Recent evidence suggests that the epoxyeicosatrienoic acids (EETs), which are products of cytochrome P450 (CYP) epoxygenases, possess mitogenic and angiogenic effects in vascular endothelial cells. However, the mechanisms underlying these effects are not fully elucidated. Because sphingosine kinase (SK) and its product S1P play essential roles in cell growth, survival and migration, we hypothesized that SK activation by EETs may mediate some of its angiogenic effects. We studied the effects of EETs on SK activity in human umbilical vein endothelial cells (HUVECs). Treatment with EETs, particularly 11,12-EET, markedly augmented SK activity in HUVECs. At the concentration of 1 micromol/L, 11,12-EET increased SK activity by 110% and the maximal effect on SK activation was observed at 20 min after 11,12-EET addition. Furthermore, inhibition of SK by a specific inhibitor, SKI-II, markedly attenuated 11,12-EET-induced EC proliferation. Importantly, 11,12-EET-induced activation of Akt kinase and transactivation of the epidermal growth factor (EGF) receptor was also inhibited by SKI-II. To investigate the isoform-specific role of SK in EET-induced angiogenesis, inhibition of SK1 by expression of dominant-negative SK1(G82D) substantiall...Continue Reading

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