Cardiovascular Research Advance Access first published online on January 10, 2008
This version [Corrected Proof] published online on March 11, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn006
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Activation of sphingosine kinase-1 mediates induction of endothelial cell proliferation and angiogenesis by epoxyeicosatrienoic acids
Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey (UMDNJ), New Jersey Medical School, 185 South Orange Avenue, MGB G-653, Newark, NJ 07103, USA
* Corresponding author. Tel: +1 973 972 7048; fax: +1 973 972 7489. E-mail address: sunj1{at}umdnj.edu; jianxin.sun{at}gmail.com
Aims: 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.
Methods and results: 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 µmol/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) substantially attenuated 11,12-EET-induced EC proliferation, migration, and tube formation in vitro and Matrigel plug angiogenesis in vivo. Furthermore, knockdown of SK1 expression by specific siRNA also inhibited 11,12-EET-induced EC proliferation and migration, whereas SK2 siRNA knockdown was without effect.
Conclusion: These results suggest that SK1 is an important mediator of the 11,12-EET-induced angiogenic effects in human ECs. Thus, SK1 may represent a novel therapeutic modality for the treatment of angiogenesis-related diseases such as cancer and ischaemia.
KEYWORDS Sphingosine kinase; Endothelial cells; Proliferation; Angiogenesis; Epoxyeicosatrienoic acids
Time for primary review: 19 days
G.Y. and S.C. contributed equally to this work.
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