Statins induce S1P1 receptors and enhance endothelial nitric oxide production in response to high‐density lipoproteins

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Abstract
Sphingosine 1-phosphate (S1P) is a serum-borne naturally occurring sphingolipid, specifically enriched in high-density lipoprotein (HDL) fractions. S1P binds to G-protein-coupled S1P1 receptors to activate endothelial NO synthase (eNOS) in vascular endothelial cells. We explored whether and how statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, modulate expression of S1P1 receptors and endothelial responses for subsequent stimulation with S1P or with HDL. Protein expression and phosphorylation and mRNA expression in cultured bovine aortic endothelial cells (BAEC) were determined using immunoblots and reverse transcription PCR analyses, respectively. NO synthesis was assessed as nitrite production. Stimulation of BAEC with pitavastatin or atorvastatin led to significant increases in S1P1-receptors, at levels of protein and mRNA, in a dose-dependent manner. When BAEC were treated with pitavastatin prior to stimulation with S1P or with normal human HDL, phosphorylation and activation of eNOS evoked by S1P or by HDL was enhanced. These effects of statins were counteracted by L-mevalonate and were mimicked by an inhibitor of geranylgeranyl transferase I, suggesting that inhibition of HMG-CoA reductase activity and subsequent decreases in protein geranylgeranylation may contribute to these actions of statins. Specific knock down of S1P1 receptors by small interfering RNA led to attenuation of eNOS responses to HDL. Statins induce S1P1 receptors and potentiate responses of endothelial cells to HDL-associated sphingolipids, identifying a novel aspect of the pleiotropic actions of statins through which they may exert NO-dependent vascular protective effects.