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

摘要: Background and purpose: 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 activate endothelial NO synthase (eNOS) vascular cells. We explored whether how statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, modulate expression of responses for subsequent stimulation with or HDL. Experimental approach: Protein phosphorylation mRNA cultured bovine aortic cells (BAEC) were determined using immunoblots reverse transcription PCR analyses, respectively. synthesis was assessed as nitrite production. Key results: Stimulation BAEC pitavastatin atorvastatin led significant increases S1P1-receptors, at levels protein mRNA, dose-dependent manner. When treated prior normal human HDL, activation eNOS evoked by HDL enhanced. These effects statins counteracted L-mevalonate mimicked an inhibitor geranylgeranyl transferase I, suggesting that inhibition HMG-CoA activity decreases geranylgeranylation may contribute these actions statins. Specific knock down small interfering RNA attenuation HDL. Conclusions implications: Statins induce potentiate HDL-associated sphingolipids, identifying novel aspect the pleiotropic through which they exert NO-dependent protective effects. British Journal Pharmacology (2007) 150, 470–479. doi:10.1038/sj.bjp.0707114