Abstract 9660: Statin-Induced Improvement of Human Endothelial Function Is Mediated by Sphingosine 1-Phosphate
Background: Endothelium is essential for maintenances of homeostasis in healthy vascular systems. Sphingosine 1-phosphate (S1P) is a potent bioactive lipid responsible for vascular protection through producing nitric oxide, whereas serotonin modulates vascular tone. Recent studies reported that bone marrow derived blood cells play a pivotal role in repairing endothelial damage. This study aimed to examine behavior of serotonin, S1P and their combined effects on endothelial function in vivo and in vitro.
Methods: Blood was withdrawn from patients without significant cardiovascular risks or medications (n=36, 40±8 years). Plasma serotonin was measured with HPLC. Plasma S1P was measured by HPLC after fluorescent derivatization with o-phthaldialdehyde. Endothelial function was assessed by flow-mediated dilation (FMD). Patients with dyslipidemia (n=14) were subsequently treated with rosuvastatin (2.5mg/day). In vitro, EA.hy926 human vascular endothelial cell line and human peripheral blood mononuclear cell (PBMC)-derived adherent cells, which were confirmed to present endothelial phenotype, were stimulated with S1P (100nmol/L) and endothelial nitric oxide synthase (eNOS) mRNA expression was examined by quantitative real-time PCR.
Results: Plasma serotonin displayed normal distribution after correction with platelets (serotonin/plt: 23.1±9.8 x10-9 pmol/platelet). Serotonin/plt inversely correlated with FMD value (3.9±1.7%, r=-0.37, P<0.05) and plasma S1P level (317.5±54.2 nmol/L, r=-0.40, P<0.05). Rosuvastatin improved lipid profiles and increased FMD after 4 weeks. Notably, percent decrease in serotonin/plt was inversely correlated with % increase in S1P (11.6±34.5%, r=-0.55, P<0.05). In vitro, EA.hy926 cells and PBMC-derived adherent cells expressed S1P receptors (S1P1, 2, 3) and sphingosine kinases (SphK1, 2). S1P (100 nmol/L), but not serotonin, stimulated eNOS mRNA expression by 1.60±0.61 fold in EA.hy926 cells (n=5) and by 1.81±0.78 fold in PBMC-derived adherent cells (n=5).
Conclusions: Increased plasma serotonin may mediate vasoconstriction and plasma S1P may provide vasculoprotection against atherogenicity of serotonin. Statin may enhance endothelial function by a novel pathway involving S1P signaling.
- © 2011 by American Heart Association, Inc.