Serum-Sphingosine-1-Phosphate Concentrations Are Inversely Associated with Atherosclerotic Diseases in Humans.

BACKGROUND AND OBJECTIVES: Atherosclerotic changes of arteries are the leading cause for deaths in cardiovascular disease and greatly impair patient's quality of life. Sphingosine-1-phosphate (S1P) is a signaling sphingolipid that regulates potentially pro-as well as anti-atherogenic processes. Here, we investigate whether serum-S1P concentrations are associated with peripheral artery disease (PAD) and carotid stenosis (CS). METHODS AND RESULTS: Serum was sampled from blood donors (controls, N = 174) and from atherosclerotic patients (N = 132) who presented to the hospital with either clinically relevant PAD (N = 102) or CS (N = 30). From all subjects, serum-S1P was measured by mass spectrometry and blood parameters were determined by routine laboratory assays. When compared to controls, atherosclerotic patients before invasive treatment to restore blood flow showed significantly lower serum-S1P levels. This difference cannot be explained by risk factors for atherosclerosis (old age, male gender, hypertension, hypercholesteremia, obesity, diabetes or smoking) or comorbidities (Chronic obstructive pulmonary disease, kidney insufficiency or arrhythmia). Receiver operating characteristic curves suggest that S1P has more power to indicate atherosclerosis (PAD and CS) than high density lipoprotein-cholesterol (HDL-C). In 35 patients, serum-S1P was measured again between one and six months after treatment. In this group, serum-S1P concentrations rose after treatment independent of whether patients had PAD or CS, or whether they underwent open or endovascular surgery. Post-treatment S1P levels were highly associated to platelet numbers measured pre-treatment. CONCLUSIONS: Our study shows that PAD and CS in humans is associated with decreased serum-S1P concentrations and that S1P may possess higher accuracy to indicate these diseases than HDL-C.

Decreased serum concentrations of sphingosine-1-phosphate in sepsis.

INTRODUCTION: Sphingosine-1-phosphate (S1P) is a signaling lipid that regulates pathophysiological processes involved in sepsis progression, including endothelial permeability, cytokine release, and vascular tone. The aim of this study was to investigate whether serum-S1P concentrations are associated with disease severity in patients with sepsis. METHODS: This single-center prospective-observational study includes 100 patients with systemic inflammatory response syndrome (SIRS) plus infection (n = 40), severe sepsis (n = 30), or septic shock (n = 30) and 214 healthy blood donors as controls. Serum-S1P was measured by mass spectrometry. Blood parameters, including C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), lactate, and white blood cells (WBCs), were determined by routine assays. The Sequential Organ Failure Assessment (SOFA) score was generated and used to evaluate disease severity. RESULTS: Serum-S1P concentrations were lower in patients than in controls (P < 0.01), and the greatest difference was between the control and the septic shock groups (P < 0.01). Serum-S1P levels were inversely correlated with disease severity as determined by the SOFA score (P < 0.01) as well as with IL-6, PCT, CRP, creatinine, lactate, and fluid balance. A receiver operating characteristic analysis for the presence or absence of septic shock revealed equally high sensitivity and specificity for S1P compared with the SOFA score. In a multivariate logistic regression model calculated for prediction of septic shock, S1P emerged as the strongest predictor (P < 0.001). CONCLUSIONS: In patients with sepsis, serum-S1P levels are dramatically decreased and are inversely associated with disease severity. Since S1P is a potent regulator of endothelial integrity, low S1P levels may contribute to capillary leakage, impaired tissue perfusion, and organ failure in sepsis.

Prostaglandin E2 does not attenuate adrenergic-induced cardiac contractile response.

Systemic inflammation may contribute to heart failure. PGE2 was recently suggested to mediate inflammation-induced impairment of cardiac function by desensitizing the murine heart to isoprenaline. Given the magnitude of the reported effect and the potential relevance, we sought to reproduce it in the human heart. Human trabeculae were prepared from the right atrial tissue obtained during heart surgery and from the right ventricle of two explanted human failing hearts. Muscle strips were electrically driven and isometric force development was measured. PGE2 was given at a single concentration (0.1 µM). Norepinephrine was used to activate ß1-adrenoceptors, epinephrine to activate ß2-adrenoceptors in atrial trabeculae. Isoprenaline was used in ventricular tissue. All patients were in sinus rhythm. Murine ventricular strips were used for comparison and stimulated with isoprenaline. The pharmacological activity of the PGE2 batch was confirmed by assessing concentration-dependent vasoconstriction in murine aorta. We used atrial and ventricular trabeculae from humans. Exposure to PGE2 (15 min) did not affect contractility when compared to time-matched controls. PGE2 neither altered the sensitivity or efficacy of ß1- or ß2-adrenoceptor-mediated stimulation of force in human atrial or in ventricular trabeculae for nonselective ß1- or ß2-adrenoceptor-stimulation. Surprisingly, PGE2 also did not affect -logEC50 values or maximum catecholamine-stimulated force in ventricular strips from mice, whereas it induced vasoconstriction in aortic rings with an -logEC50 of 5.0 (n = 6). Our data do not support a role for PGE2 in regulating catecholamine inotropy, neither in mice nor in humans.