Abstract
Sphingolipids are structural components of cell membrane, displaying several functions in cell signalling. Extracellular vesicles (EV) are lipid bilayer membrane nanoparticle and their lipid composition may be different from parental cells, with a significant enrichment in sphingolipid species, especially in pathological conditions. We aimed at optimizing EV isolation from plasma and describing the differential lipid content of EV, as compared to whole plasma. As pilot study, we evaluated the diagnostic potential of lipidomic signature of circulating EV in patients with a diagnosis of ST-segment-elevation myocardial infarction (STEMI). STEMI patients were evaluated before reperfusion and 24-h after primary percutaneous coronary intervention. Twenty sphingolipid species were quantified by liquid-chromatography tandem-mass-spectrometry. EV-ceramides, -dihydroceramides, and -sphingomyelins increased in STEMI vs. matched controls and decreased after reperfusion. Their levels correlated to hs-troponin, leucocyte count, and ejection fraction. Plasma sphingolipids levels were 500-to-700-fold higher as compared to EV content; nevertheless, only sphingomyelins differed in STEMI vs. control patients. Different sphingolipid species were enriched in EV and their linear combination by machine learning algorithms accurately classified STEMI patients at pre-PCI evaluation. In conclusion, EV lipid signature discriminates STEMI patients. These findings may contribute to the identification of novel biomarkers and signaling mechanisms related to cardiac ischemia.
Highlights
Sphingolipids are structural components of cell membrane, displaying several functions in cell signalling
multivesicular bodies (MVB) biogenesis and membrane budding, results in topological similarity between donor cell and released vesicles membranes, major differences exist in the lipid composition of such released vesicles when compared with whole cell lipid extract of parental cells, demonstrating the existence of specific mechanisms of lipid sorting into E V13
percutaneous coronary intervention (PCI) was performed within 1 h from the first medical contact for all segment-elevation myocardial infarction (STEMI) patients
Summary
Sphingolipids are structural components of cell membrane, displaying several functions in cell signalling. The ischemic process leads to membrane depolarization, with activation of voltage-dependent calcium-channels, increase of intracellular calcium concentration, and activation of calcium-dependent lipases and phospholipases[5] Enzymes such as ceramidase and sphingomyelinase responsible for catalyzing the metabolism of cell membrane structural lipids (ceramide and sphingomyelin respectively) contribute to membrane disruption and cardiomyocytes apoptosis[5,10]. In light of such evidences, these processes may affect the blood lipidomic profile in patient experiencing myocardial injury. In this study we employed UC isolation protocol to obtain plasma-derived EV in order to guarantee specificity without compromising yield[26], while further optimizing the reduction of cross-contamination, as previously r eported[27,28]
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