Signaling roles of sphingolipids in the ischemic brain and their potential utility as therapeutic targets

 But what about this problem with sphingolipids? Hasn't your competent? doctor initiated research to solve this? NO? So you DON'T have a functioning stroke doctor, do you?

Sphingolipids Contribute to Human Atherosclerotic Plaque Inflammation May 2016

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Signaling roles of sphingolipids in the ischemic brain and their potential utility as therapeutic targets

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https://doi.org/10.1016/j.nbd.2024.106682

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Highlights

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  Ischemic stroke leads to dysregulation of the sphingolipid metabolism.
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  Ceramide accumulation occurring post-stroke deteriorates injury and inhibiting its metabolizing enzymes enhances recovery.
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  S1P receptor modulation influences vascular function and immune cell trafficking post-stroke.
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  Sphingolipids are important for the formation and release of extracellular vesicles that stimulate brain remodeling.

Abstract

Sphingolipids comprise a class of lipids, which are composed of a sphingoid base backbone and are essential structural components of cell membranes. Beyond their role in maintaining cellular integrity, several sphingolipids are pivotally involved in signaling pathways controlling cell proliferation, differentiation, and death. The brain exhibits a particularly high concentration of sphingolipids and dysregulation of the sphingolipid metabolism due to ischemic injury is implicated in consecutive pathological events. Experimental stroke studies revealed that the stress sphingolipid ceramide accumulates in the ischemic brain post-stroke. Specifically, counteracting ceramide accumulation protects against ischemic damage and promotes brain remodeling, which translates into improved behavioral outcome. Sphingomyelin substantially influences cell membrane fluidity and thereby controls the release of extracellular vesicles, which are important vehicles in cellular communication. By modulating sphingomyelin content, these vesicles were shown to contribute to behavioral recovery in experimental stroke studies. Another important sphingolipid that influences stroke pathology is sphingosine-1-phosphate, which has been attributed a pro-angiogenic function, that is presumably mediated by its effect on endothelial function and/or immune cell trafficking. In experimental and clinical studies, sphingosine-1-phosphate receptor modulators allowed to modify clinically significant stroke recovery. Due to their pivotal roles in cell signaling, pharmacological compounds modulating sphingolipids, their enzymes or receptors hold promise as therapeutics in human stroke patients.

Keywords

Ceramide

Sphingomyelin

Sphingosine-1-phosphate

Ischemic stroke

1. Introduction

1.1. Functional roles of sphingolipids

Sphingolipids are enriched in cellular membranes, but their roles extend far beyond their function as mere structural elements. In comparison to other organs such as heart, spleen and liver, the concentration of the sphingolipids is particularly high in the brain and dysregulation of the sphingolipid metabolism is implicated in neurodegenerative disorders (Muralidharan et al., 2021; Piccinini et al., 2010).

Ceramide is structurally one of the simplest sphingolipid and is considered to be the most studied one. It consists of a sphingoid base, which is linked via an amide bond to a fatty acid (Alonso and Goni, 2018). Ceramide signaling is activated by several stress stimuli such as radiation, UV light or inflammatory cytokines like tumor necrosis factor (TNF) (Chatterjee and Wu, 2001; Martinez et al., 2012; Vit and Rosselli, 2003). Ceramide-rich platforms on cell membranes enable protein oligomerization in order to amplify transmembrane signaling (Stancevic and Kolesnick, 2010). These platforms are critically involved in apoptotic events. CD95 clustering on ceramide-rich platforms for instance precedes death-inducing signaling complex (DISC) formation and caspase activation (Grassme et al., 2003). In view of the importance of ceramide for pro-apoptotic pathways, pharmacological inhibition of ceramide formation was shown to increase cell survival under pathological conditions (Gulbins et al., 2013). More complex ceramide derivates such as galactosylceramide are essential components of myelin sheaths that insulate axons enabling fast transmission of electric impulses (Zoller et al., 2008). Galactosylceramide deficiency causes demyelination which consequently leads to severe impairment of motor coordination (Coetzee et al., 1996; Zoller et al., 2005), which again emphasizes the functional relevance of sphingolipids.

After binding to specific G protein-coupled receptors, bioactive sphingolipids such as sphingosine-1-phosphate (S1P) function as signaling molecules and stimulate the activation of complex cascades, which govern cellular processes such as cell migration and angiogenesis (Blaho and Hla, 2014). Treatment with S1P increases vascular density and further amplifies VEGF-induced angiogenesis (Lee et al., 1999a). S1P also stimulates the assembly of adherens junctions on endothelial cells by activating Rac/ Rho signaling (Lee et al., 1999a). Further, S1P has been attributed an anti-apoptotic effect (Lee et al., 1999a).

Sphingolipids are further implicated in cellular mechanisms that control the endocytic trafficking machinery. Release of exosomes can be reduced by inhibition of neutral sphingomyelinase (NSM)-mediated sphingomyelin hydrolysis using GW4869, spiroepoxide or glutathione (Trajkovic et al., 2008). Disturbed exosome release due to reduced ceramide likely occurs because ceramide-enriched domains facilitate the sorting of cargo destined for exosomal release into multivesicular bodies and inhibition of NSM substantially reduces the amount of specific cargo within the endosomal lumen (Trajkovic et al., 2008). Exosomes that are generated via this endosomal sorting complexes required for transport (ESCRT)-independent pathway typically exhibit a high ceramide content (Trajkovic et al., 2008). Moreover, hydrolysis of sphingomyelin leads to formation of early endocytic intermediates to which sphingosine kinase-1 is recruited, the enzyme that catalyzes phosphorylation of sphingosine to S1P (Shen et al., 2014). The importance of sphingosine kinase-1 for endosomal recycling is depicted by experiments showing that its knockdown causes accumulation of internalized transferrin, which is indicative for endosomal recycling defects (Shen et al., 2014). Further, sphingolipids may alter lysosomal function. Accumulation of unmetabolized sphingolipids results in severe pathological conditions as genetic deficiency of specific enzymes that regulate the sphingolipid metabolism are causative for lysosomal storage disorders that lead to dysfunctional lysosomes and impaired autophagic flux (Carsana et al., 2022; Platt et al., 2012). Niemann-Pick disease type-A, for example, is a severe neurodegenerative disorder associated with early childhood mortality and is caused by inherited acid sphingomyelinase (ASM) deficiency, which leads to accumulation of sphingomyelin in lysosomes (Horinouchi et al., 1995).

Given the importance of sphingolipids for pivotal cellular processes, this review aims to depict the signaling roles of prominent sphingolipids, namely ceramide, sphingomyelin and S1P, for pathological events following ischemic stroke. Another focus of this review is to outline how sphingolipids may serve as targets for potential therapeutic interventions.

 

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Sphingolipids Contribute to Human Atherosclerotic Plaque Inflammation

So what is the solution? Don't just describe a problem, at least suggest a solution.
Sphingolipids Contribute to Human Atherosclerotic Plaque Inflammation

1. Andreas Edsfeldt*,
2. Pontus Dunér*,
3. Marcus Ståhlman,
4. Ines G. Mollet,
5. Giuseppe Asciutto,
6. Helena Grufman,
7. Mihaela Nitulescu,
8. Ana Flor Persson,
9. Rachel M. Fisher,
10. Olle Melander,
11. Marju Orho-Melander,
12. Jan Borén,
13. Jan Nilsson,
14. Isabel Gonçalves

+ Author Affiliations

1. From the Experimental Cardiovascular Research Unit, Clinical Research Centre, Clinical Sciences Malmö, Lund University, Malmö, Sweden (A.E., P.D., G.A., H.G., M.N., A.F.P., J.N., I.G.); Vascular Centre Malmö-Lund, Skåne, University Hospital, Malmö, Sweden (G.A.); Department of Cardiology, Skåne University Hospital, Lund/Malmö, Sweden (A.E., H.G., A.F.P., I.G.); Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska University Hospital University, Gothenburg, Sweden (M.S., J.B.); Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Solna, Sweden (R.M.F.); and Department of Clinical Sciences Malmö, Clinical Research Center, Lund University, Malmö, Sweden (I.G.M., O.M., M.O.-M.).

1. Correspondence to Andreas Edsfeldt, MD, PhD, Clinical Research Center, Entrance 72, House 91, plan 12, Malmö University Hospital, SE-20502 Malmö, Sweden. E-mail Andreas.Edsfeldt@med.lu.se

1. ↵* These authors contributed equally to this article.

Abstract

Objective—Lipids are central to the development of atherosclerotic plaques. Specifically, which lipids are culprits remains controversial, and promising targets have failed in clinical studies. Sphingolipids are bioactive lipids present in atherosclerotic plaques, and they have been suggested to have both proatherogenic and antiatherogenic. However, the biological effects of these lipids remain unknown in the human atherosclerotic plaque. The aim of this study was to assess plaque levels of sphingolipids and investigate their potential association with and contribution to plaque vulnerability.

Approach and Results—Glucosylceramide, lactosylceramide, ceramide, dihydroceramide, sphingomyelin, and sphingosine-1-phosphate were analyzed in homogenates from 200 human carotid plaques using mass spectrometry. Inflammatory activity was determined by analyzing plaque levels of cytokines and plaque histology. Caspase-3 was analyzed by ELISA technique. Expression of regulatory enzymes was analyzed with RNA sequencing. Human coronary artery smooth muscle cells were used to analyze the potential role of the 6 sphingolipids as inducers of plaque inflammation and cellular apoptosis in vitro. All sphingolipids were increased in plaques associated with symptoms and correlated with inflammatory cytokines. All sphingolipids, except sphingosine-1-phosphate, also correlated with histological markers of plaque instability. Lactosylceramide, ceramide, sphingomyelin, and sphingosine-1-phosphate correlated with caspase-3 activity. In vitro experiments revealed that glucosylceramide, lactosylceramide, and ceramide induced cellular apoptosis. All analyzed sphingolipids induced an inflammatory response in human coronary artery smooth muscle cells.

Conclusions—This study shows for the first time that sphingolipids and particularly glucosylceramide are associated with and are possible inducers of plaque inflammation and instability, pointing to sphingolipid metabolic pathways as possible novel therapeutic targets.