Plasma lipidomic analysis of sphingolipids in patients with large artery atherosclerosis cerebrovascular disease and cerebral small vessel disease

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Abstract

Background: Sphingolipids mainly consist of ceramides (Cer), sphingomyelins (SM) and glycosphingolipids. Sphingolipids are related with coronary heart disease and metabolic disease, but there’re few studies about cerebrovascular disease. The purpose was to detect sphingolipids in plasma of patients with large artery atherosclerosis (LAA) cerebrovascular disease and cerebral small vessel disease (CSVD) to explore the similarities and differences of pathogenesis of the two subtypes.

Methods: 20 patients with LAA cerebrovascular disease, 20 patients with age-related CSVD, 10 patients with Fabry disease and 14 controls were enrolled from October 2017 to January 2019. Ultra-high performance liquid chromatography-quadruple-time-of-flight mass spectrometry/mass spectrometry was used to determine sphingolipids. Univariate combined with multivariate analysis was used for comparison. Receiver operating characteristic curves were used to determine sensitivities and specificities.

Results: 276 sphingolipids were detected, including 39 Cer, 3 ceramide phosphates, 72 glycosphingolipids and 162 SM. (1) Cer (d36:3), Cer (d34:2), Cer (d38:6), Cer (d36:4) and Cer (d16:0/18:1) were increased in LAA; SM (d34:1), Cer (d34:2), Cer (d36:4), Cer (d16:0/18:1), Cer (d38:6), Cer (d36:3) and Cer (d32:0) were increased in age-related CSVD. (2) Cer (d36:4) and SM (d34:1) were increased in age-related CSVD compared with LAA. (3) Total trihexosyl ceramides were increased in Fabry group compared with control ( P<0.05); SM (d34:1) was increased in Fabry group.

Conclusions: Ceramides are increased in both LAA and age-related CSVD, which may be related to similar risk factors and pathophysiological process of arteriosclerosis; SM is increased in both age-related CSVD and Fabry disease, suggesting that increased SM may be associated with CSVD. Glycosphingolipids, trihexosylceramides in particular, are increased in Fabry disease.

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Sphingolipids: membrane microdomains in brain development, function and neurological diseases

Anne S B Olsen, Nils Færgeman (2017)

Sphingolipids are highly enriched in the nervous system where they are pivotal constituents of the plasma membranes and are important for proper brain development and functions. Sphingolipids are not merely structural elements, but are also recognized as regulators of cellular events by their ability to form microdomains in the plasma membrane. The significance of such compartmentalization spans broadly from being involved in differentiation of neurons and synaptic transmission to neuronal–glial interactions and myelin stability. Thus, perturbations of the sphingolipid metabolism can lead to rearrangements in the plasma membrane, which has been linked to the development of various neurological diseases. Studying microdomains and their functions has for a long time been synonymous with studying the role of cholesterol. However, it is becoming increasingly clear that microdomains are very heterogeneous, which among others can be ascribed to the vast number of sphingolipids. In this review, we discuss the importance of microdomains with emphasis on sphingolipids in brain development and function as well as how disruption of the sphingolipid metabolism (and hence microdomains) contributes to the pathogenesis of several neurological diseases.

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Ceramide: a simple sphingolipid with unique biophysical properties.

Bruno de Castro, Manuel J Prieto, Liana Silva (2014)

Ceramides are involved in a variety of cellular processes and in disease. Their biological functions are thought to depend on ceramides' unique biophysical properties, which promote strong alterations of cell membrane properties and consequent triggering of signaling events. Over the last decades, efforts were made to understand the impact of ceramide on membrane biophysical features. Several studies, performed in a multitude of membrane models, address ceramides' specific interactions, the effect of their acyl chain structure and the influence of membrane lipid composition and properties on ceramide biophysical outcome. In this review, a rationale for the multiple and complex changes promoted by ceramide is provided, highlighting, on a comprehensive and critical manner, the interactions between ceramides and specific lipids and/or lipid phases. Focus is also given to the interplay between ceramide and cholesterol, particularly in lipid raft-mimicking mixtures, an issue of intense debate due to the urgent need to understand the biophysical impact of ceramide formation in models resembling the cell membrane. The implications of ceramide-induced biophysical changes on lipid-protein interactions and cell signaling are also discussed, together with the emerging evidence for the existence of ceramide-gel like domains in cellular membranes.

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Ceramide Mediates Vascular Dysfunction in Diet-Induced Obesity by PP2A-Mediated Dephosphorylation of the eNOS-Akt Complex

Quan-Jiang Zhang, William Holland, Lloyd Wilson … (2012)

Vascular dysfunction that accompanies obesity and insulin resistance may be mediated by lipid metabolites. We sought to determine if vascular ceramide leads to arterial dysfunction and to elucidate the underlying mechanisms. Pharmacological inhibition of de novo ceramide synthesis, using the Ser palmitoyl transferase inhibitor myriocin, and heterozygous deletion of dihydroceramide desaturase prevented vascular dysfunction and hypertension in mice after high-fat feeding. These findings were recapitulated in isolated arteries in vitro, confirming that ceramide impairs endothelium-dependent vasorelaxation in a tissue-autonomous manner. Studies in endothelial cells reveal that de novo ceramide biosynthesis induced protein phosphatase 2A (PP2A) association directly with the endothelial nitric oxide synthase (eNOS)/Akt/Hsp90 complex that was concurrent with decreased basal and agonist-stimulated eNOS phosphorylation. PP2A attenuates eNOS phosphorylation by preventing phosphorylation of the pool of Akt that colocalizes with eNOS and by dephosphorylating eNOS. Ceramide decreased the association between PP2A and the predominantly cytosolic inhibitor 2 of PP2A. We conclude that ceramide mediates obesity-related vascular dysfunction by a mechanism that involves PP2A-mediated disruption of the eNOS/Akt/Hsp90 signaling complex. These results provide important insight into a pathway that represents a novel target for reversing obesity-related vascular dysfunction.

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Contributors

Yining Huang:

ORCID: http://orcid.org/0000-0002-1657-4151

Journal

Journal ID (nlm-ta): Biosci Rep

Journal ID (iso-abbrev): Biosci. Rep

Journal ID (publisher-id): bsr

Title: Bioscience Reports

Publisher: Portland Press Ltd.

ISSN (Print): 0144-8463

ISSN (Electronic): 1573-4935

Publication date Collection: 30 September 2020

Publication date (Electronic): 18 September 2020

Volume: 40

Issue: 9

Electronic Location Identifier: BSR20201519

Affiliations

Department of Neurology, Peking University First Hospital 100034, Beijing, China

Author notes

Correspondence: Yining Huang ( ynhuang@ 123456sina.com )

[*]

These authors contributed equally to this work.

Author information

Zemou Yu http://orcid.org/0000-0002-9658-4869

Yining Huang http://orcid.org/0000-0002-1657-4151

Article

Publisher ID: BSR20201519

DOI: 10.1042/BSR20201519

PMC ID: 7502657

PubMed ID: 32830858

SO-VID: 9e199f84-0f14-444e-9dcf-003cedbbf3e2

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This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

History

Date received : 08 May 2020

Date revision received : 11 August 2020

Date accepted : 19 August 2020

Date: 24 August 2020

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Pages: 11

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Plasma lipidomic analysis of sphingolipids in patients with large artery atherosclerosis cerebrovascular disease and cerebral small vessel disease

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Most cited references 31

Sphingolipids: membrane microdomains in brain development, function and neurological diseases

Ceramide: a simple sphingolipid with unique biophysical properties.

Ceramide Mediates Vascular Dysfunction in Diet-Induced Obesity by PP2A-Mediated Dephosphorylation of the eNOS-Akt Complex

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