α-Tocopheryl Phosphate Induces VEGF Expression via CD36/PI3Kγ in THP-1 Monocytes.

The CD36 scavenger receptor binds several ligands and mediates ligand uptake and ligand-dependent signal transduction and gene expression, events that may involve CD36 internalization. Here we show that CD36 internalization in THP-1 monocytes is triggered by alpha-tocopherol (alpha T) and more strongly by alpha-tocopheryl phosphate (alpha TP) and EPC-K1, a phosphate diester of alpha TP and L-ascorbic acid. alpha TP-triggered CD36 internalization is prevented by the specific covalent inhibitor of selective lipid transport by CD36, sulfo-N-succinimidyl oleate (SSO). Moreover, SSO inhibited the CD36-mediated uptake of 14C-labelled aTP suggesting that aTP binding and internalization of CD36 is involved in cellular alpha TP uptake, whereas the uptake of alpha T was less affected. Similar to that, inhibition of selective lipid transport of the SR-BI scavenger receptor resulted mainly in reduction of alpha TP and not alpha T uptake. In contrast, uptake of alpha T was mainly inhibited by Dynasore, an inhibitor of clathrin-mediated endocytosis, suggesting that the differential regulatory effects of alpha TP and alpha T on signaling may be influenced by their different routes of uptake. Interestingly, alpha TP and EPC-K1 also reduced the neutral lipid content of THP-1 cells and the phagocytosis of fluorescent Staphylococcus aureus bioparticles. Moreover, induction of the vascular endothelial growth factor (VEGF) promoter activity by aTP occurred via CD36/PI3K gamma/Akt, as it could be inhibited by specific inhibitors of this pathway (SSO, Wortmannin, AS-605240). These results suggest that aTP activates PI3K gamma/Akt signaling leading to VEGF expression in monocytes after binding to and/or transport by CD36, a receptor known to modulate angiogenesis in response to amyloid beta, oxLDL, and thrombospondin. (C) 2017 Wiley Periodicals, Inc.