Abstract 12757: HDAC 7 Couples LPA Signaling to Endothelial Cell CD36 Gene Regulation to Switch off TSP-1 Mediated Antiangiogenic Responses
CD36 is a microvascular endothelial cell (MVEC) receptor mediating the angiostatic activity of TSP-1 related proteins. We previously reported that lysophosphatidic acid (LPA), a biologically active extracellular lipid signaling mediator, down-regulated MVEC CD36 expression in vitro via a PKD-1 signaling pathway initiated by G-protein coupled LPA receptors LPA1 and LPA3. We now demonstrate by actinomycin D treatment that there were no differences in CD36 mRNA stability between LPA treated and control cells, whereas nuclear run-on experiments showed major inhibition of CD36 gene transcription after LPA exposure. To determine the molecular mechanisms underlying CD36 transcriptional control by LPA we studied the impact of LPA on the class II histone deacetylase HDAC7 and the transcription factors FoxO1 and Nur77. LPA exposure for 24hr increased nuclear accumulation of Nur77 and PKD-1 and enhanced expression and export of HDAC7. We saw significant acetylation of histone 2B lysine 5 in MVEC and found that LPA exposure for 16 or 24hr led to its deacetylation. This time course corresponds with the change of MVEC CD36 expression. Immunofluorescence microscopy of FGF-2 driven in vivo matrigel angiogenesis assays in mice showed reduced CD36 expression in the neovasculature in the presence of LPA. The functional significance of this reduction was demonstrated by showing blunted response to TSP-1 in matrigel plugs containing LPA. Moreover western blots showed that FGF-2 was still able to stimulate Akt activation in the presence of TSP-1 in MVEC pretreated with LPA for 22hr. These data show that microvascular endothelial cells may lose sensitivity to TSP-1 mediated antiangiogenesis via transcriptional down-regulation of the critical receptor, CD36. Mechanistically, HDAC7 modulation by the LPA receptor/PKD-1 signaling pathway may be an important link in the transcriptional regulation, suggesting that epigenetic downregulation of CD36 expression could permanently turn off this antiangiogenic switch. Since LPA is produced abundantly during inflammation and by activated platelets and some tumor cells, targeting the LPA-PKD-CD36 axis could have potential therapeutic implications.
- © 2010 by American Heart Association, Inc.