An involvement of SR-B1 mediated PI3K–Akt–eNOS signaling in HDL-induced cyclooxygenase 2 expression and prostacyclin production in endothelial cells

It is well-known that sphingosine-1-phosphate (S1P), the phospholipid content of HDL, binding to S1P receptors can raise COX-2 expression and PGI2 release through p38MAPK/CREB pathway. In the present study we assess the action of SR-B1 initiated PI3K–Akt–eNOS signaling in the regulation of COX-2 expression and PGI2 production in response to HDL. We found that apoA1 could increase PGI2 release and COX-2 expression in ECV 304 endothelial cells. Furthermore, SR-B1 was found to be involved in HDL induced up-regulation of COX-2 and PGI2. Over-expressed SR-B1 did not significantly increase the expression of COX-2 and the PGI2 levels, but knock-down of SR-B1 by siRNA could significantly attenuate COX-2 expression and PGI2 release together with p38MAPK and CREB phosphorylation. Consistently, the declines of p-p38MAPK, p-CREB, COX-2 and PGI2 were also observed after incubation with LY294002 (25 μmol/L; PI3K special inhibitor) or L-NAME (50 μmol/L; eNOS special inhibitor). In addition, we demonstrated the increases of PGI2 release, COX-2 expression and p38MAPK phosphorylation, when nitric oxide level was raised through the incubation of L-arginine (10 or 20 nmol/L) in endothelial cells. Taking together, our data support that SR-B1 mediated PI3K–Akt–eNOS signaling was involved in HDL-induced COX-2 expression and PGI2 release in endothelial cells.

► SR-B1–PI3K–Akt–eNOS signaling was implicated in HDL-induced COX-2 and PGI2.
► SR-B1 siRNA down-regulated p-p38MAPK, p-CREB, COX-2 and PGI2.
► And p-p38MAPK, p-CREB, COX-2 and PGI2 were decreased after inhibiting PI3K or eNOS.
► With the raising of NO, an increase of p-p38MAPK, p-CREB, COX-2 and PGI2 were found.