Abstract 9346: Imbalance Between Plasma Serotonin and Sphingosine 1-Phosphate is a Novel Therapeutic Target of Statins in Patients with Early Atherosclerosis
Background: Serotonin derived from enterochromaffin cells is incorporated to platelets and modulates vascular tone. Conversely, sphingosine 1-phosphate (S1P) is a potent bioactive lipid responsible for vascular cell protection through producing nitric oxide (NO). We aimed to determine the behavior of serotonin, S1P, and their combined effects on vascular function in vivo.
Methods: Blood was taken from patients with low or moderate cardiovascular risks (n=35, 40±8 years) without overt cardiovascular disease or medications. Serotonin levels in plasma, i.e. serotonin derived from platelets, were measured with HPLC. S1P levels in plasma were also measured by HPLC after fluorescent derivatization with o-phthaldialdehyde. Endothelium-dependent dilation, a marker of endothelial function, was measured by flow-mediated dilation (FMD) and endothelium-independent dilation was measured by nitroglycerin-induced dilation (NID) using ultrasound system. Patients with dyslipidemia (LDL 141±19 mg/dl, HDL 52±8 mg/dl, TG 200±78 mg/dl, n=14) were subsequently treated with rosuvastatin (2.5 mg/day) for 4 weeks.
Results: Plasma serotonin displayed normal distribution after correction with platelets numbers (serotonin/plt: 22.2±8.4 × 10−9 pmol/platelet). Serotonin/plt inversely correlated with FMD (3.9±1.7%, r=−0.391, p<0.05) and plasma S1P (318±54 nmol/L, r=−0.401, p<0.05). Rosuvastatin improved dyslipidemia (LDL 89±33 mg/dl, HDL 57±12 mg/dl, TG 155±79 mg/dl) and increased FMD (3.7±1.6% to 5.7±2.0%, p<0.01). NID was unchanged. Percent decrease in serotonin/plt (6.1±43.6%) with statin was inversely correlated with % increase in S1P (11.6±34.5%, r=−0.552, p<0.05). In EA.hy926 human vascular endothelial cell line S1P receptors (S1P1, 2, 3) were expressed and S1P (100 nmol/L) stimulated endothelial NO synthase mRNA expression by1.60±0.61 fold (n=3) (quantitative real-time PCR).
Conclusions: This is the first clinical evidence that increased plasma serotonin may mediate vasoconstriction and plasma S1P may provide vasculoprotection against atherogenicity of serotonin in vivo in humans. More importantly, amelioration of imbalance between serotonin and S1P represents another mechanism that explains the pleiotropic actions of statins.
- © 2010 by American Heart Association, Inc.