Sphingosine-1-phosphate receptors 1 and 3 regulate the expression of SR-B1 in human aortic endothelial cells

Abstract

Several vasoprotective functions of high-density lipoproteins (HDL) on the endothelium have been shown to depend on the presence of sphingosine-1-phosphate (S1P) receptors (S1PRs) as well as scavenger receptor class B type 1 (SR-B1). Interference with the presence of S1P or the activity of S1PR1 or S1PR3 mimics many effects seen by the interference with SR-B1. This raises the question on interactions between S1P receptors and SR-B1. We investigated the influence of S1PRs on SR-B1 expression in human aortic endothelial cells. Silencing or pharmacological inhibition of S1PR1 or S1PR3 down-regulated SCARB1 mRNA expression as well as SR-B1 protein abundance. RNA interference with S1PR1 or S1PR3 also decreased cellular association of 125I-HDL with HAECs. Further mechanistic studies showed that knockdown of S1PR1 or S1PR3 reduced SR-B1 protein by inducing its degradation through deceasing Akt activity. Moreover, silencing of S1PR1 or S1PR3 suppressed SCARB1 mRNA expression by decreasing cellular cAMP levels. In conclusion, we provide evidence for an as yet unappreciated interaction, namely the regulation of SR-B1 abundance by S1PRs on both transcriptional and post-translational levels, suggesting that interactions of S1PRs and SR-B1 regulate signaling functions of HDL as well as uptake of lipoproteins in endothelial cells.