Inverse relationship between circulating sphingosine-1-phosphate and precursor species and coronary artery...

Sphingosine 1-phosphate (S1P) is a key mediator of lipid signaling with strong immunomodulatory and anti-inflammatory effects. Circulating S1P levels including S1P in high-density lipoproteins (HDL) were demonstrated to be inversely associated with cardiovascular diseases (CVD). However, no studies are available regarding a potential implication of S1P on the risk of CVD in type 2 diabetes (T2D). The objective of this study is to determine if the increased CVD risk in T2D may involve an alteration of circulating S1P species as well as their precursors.

A total of 168 and 31 patients with T2D (154 men and 45 women) with available Coronary artery calcification (CAC) score from the DIACART and CERABIAB cohorts, respectively, were included in the study. Quantification of S1P species and their precursors was carried out by LC-MS/MS in plasma and isolated HDL. CAC score was modeled as a binary variable (0/1 below or equal/above 100) using CAC < 100 for reference. S1P species or precursors were modeled as binary variables dichotomized at the median (0/1: below or equal/above the median). The relationships between S1P species and CAC score modeled as a binary variable (below or equal/above 100) was evaluated by linear regression analyses. In vitro experiments were conducted to evaluate the contribution of HDL-S1P content on anti-inflammatory properties of HDL particles.

Multivariate analysis revealed that plasma S1P levels, especially d18:1-S1P, and sphingosine in HDL were inversely associated with the high risk of CVD (CAC > 100) in patients with T2D. Clustering of HDL according to their concentration in S1P species and their precursors revealed that S1P-impoverished HDL is a major feature of patients with a CAC > 100. In vitro analysis of monocyte adhesion and inflammation in human umbilical vein endothelial cells as well as inflammatory phenotype of human macrophages demonstrated that low HDL-S1P exhibited impaired anti-inflammatory properties in comparison to high HDL-S1P.

This study unraveled that circulating S1P and their precursors are biomarkers of coronary atherosclerosis in T2D, which may underlie the lower abundance of S1P and anti-inflammatory activities of HDL. Trial registration ClinicalTrials.gov number, NCT02431234.