Plasma Sphingolipid Profile Associated With Subclinical Atherosclerosis and Clinical Disease Markers of Systemic Lupus Erythematosus: Potential Predictive Value

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects females more than males, with African Americans developing more severe manifestation of the disease. SLE patients are at increased risk for cardiovascular disease (CVD), and SLE women 35-44 years old have 50 fold the incidence rate of CVD. Because SLE patients do not follow the typical age and gender pattern for CVD, but instead an accelerated disease course, the traditional biomarkers of elevated LDL and total cholesterol levels do not accurately assess their CVD risk. Recently, we have reported that African American SLE patients had higher ceramide, hexosylceramide, sphingosine and dihydrosphingosine 1-phosphate levels compared to their healthy controls, and those with atherosclerosis had higher sphingomyelin and sphingoid bases levels than those without (PLoS One. 2019; e0224496). In the current study, we sought to identify sphingolipid species that correlate with and pose the potential to predict atherosclerosis severity in African American SLE patients. Plasma samples from a group of African American predominantly female SLE patients with well-defined carotid atherosclerotic plaque burden were analyzed for sphingolipidomics using targeted mass spectroscopy. The data demonstrated that at baseline, plaque area and C3 values correlated inversely with most lactoceramide species. After one-year follow-up visit, values of the change of plaque area correlated positively with the lactoceramide species. There was no correlation between LDL-C concentrations and lactoceramide species. Taken together, lactocylcermide levels may have a ‘predictive’ value and sphingolipidomics have an added benefit to currently available tools in early diagnosis and prognosis of African American SLE patients with CVD.

Multi-Platform Omics Analysis Reveals Molecular Signatures for Pathogenesis and Activity of Systemic Lupus Erythematosus

“…Among them, glucosylceramide and SM levels were also associated with SLE disease score ( Supplementary Figure 6B ). Consistently, sphinganine and SM were reported to be changed in SLEs and related to complications, thus supporting our data ( 20 ). These data show the potential value of assessing sphingolipid changes in SLEs, especially in the HA group, and supports the use of sphingolipidomics as a tool to pinpoint a biomarker for early identification ( 12 ).…”

An Update on Sphingolipidomics: Is Something Still Missing? Some Considerations on the Analysis of Complex Sphingolipids and Free-Sphingoid Bases in Plasma and Red Blood Cells

“…When we adopted the final extraction protocol (Materials and Methods, Section 3.4 , protocol 4), for both complex sphingolipids and sphingoid bases (long chromatography on Cortecs C18), the concentration range of the analytes fell perfectly into those described in the literature [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ] and the reproducibility of the methods was validated ( Table 1 and Table 2 ). In Figure 4 , the attained ranges are shown.…”

“…One of the main issues in the analysis of Sph and other sphingoid bases is that their levels in plasma and other biological matrices are not always high enough to allow a precise quantitation. Bearing in mind that the concentrations of sphingoid bases in human plasma range from 0.006 µM to 1.56 µM [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ] ( Supplementary Figure S1 ), it is critical to be aware of any possible interferents in the analysis. As particularly appraisable in Figure 3 , choosing the appropriate column and chromatography conditions can make a huge difference in sphingoid bases analysis.…”

“… ( A ) Quantification of sphingolipids in a plasma pool from healthy volunteers ( n = 20) as a function of different extraction protocols and comparison to the reference values found in the scientific literature. On the left of the heatmap, the range of concentration (µM) of sphingolipids in plasma EDTA from healthy volunteers found in the scientific literature [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. For visualization, data were scaled to reference values and reported as a fold-change logarithm.…”

Sex Differences in Cardiovascular Diseases: A Matter of Estrogens, Ceramides, and Sphingosine 1-Phosphate

“…In particular, these authors observed a positive association between plasma PhE concentration (mainly equol and enterolactone) and the prevention of hypertension. Other studies, including the report from Hammad and colleagues [ 185 ] demonstrated that the usage of resveratrol during the post-menopausal period is a valid and safer alternative to Es to prevent vascular calcification. Finally, Wolters et al [ 186 ] defined the effects of PhE supplementation in postmenopausal women in a metanalysis of randomized controlled trials.…”