Elsevier

Clinica Chimica Acta

Volume 521, October 2021, Pages 25-33
Clinica Chimica Acta

Review
Sphingosine 1-phosphate and its receptors in ischemia

https://doi.org/10.1016/j.cca.2021.06.020Get rights and content

Abstract

Sphingosine 1-phosphate (S1P), a metabolite of sphingolipids, is mainly derived from red blood cells (RBCs), platelets and endothelial cells (ECs). It plays important roles in regulating cell survival, vascular integrity and inflammatory responses through its receptors. S1P receptors (S1PRs), including 5 subtypes (S1PR1-5), are G protein-coupled receptors and have been proved to mediate various and complex roles of S1P in atherosclerosis, myocardial infarction (MI) and ischemic stroke by regulating endothelial function and inflammatory response as well as immune cell behavior. This review emphasizes the functions of S1PRs in atherosclerosis and ischemic diseases such as MI and ischemic stroke, enabling mechanistic studies and new S1PRs targeted therapies in atherosclerosis and ischemia in the future.

Introduction

Atherosclerosis is a systemic pathological change initiated by endothelial dysfunction for inflammation and high levels of low-density lipoprotein (LDL), and then accompanied by deposition of lipids and the formation of plaques on arterial walls. Atherosclerosis generally leads to arterial lumen stenosis, and in some cases ruptured plaques form thrombus, thus leading to partial or total occlusion of the artery, interruption of blood flow and ischemia [1], [2]. Hence, the main clinical manifestations of atherosclerosis include myocardial infarction (MI), ischemic stroke, and peripheral artery disease [3]. Atherosclerotic lesions in the coronary arteries lead to MI, which ultimately leads to impaired cardiac function [4]. In turn, MI accelerates atherosclerosis by recruiting monocytes [5]. Cerebral infarction, also known as ischemic stroke, is another high-incidence infarction disease in people with atherosclerosis. Patients may suffer from mobility impairment, dysfunction of consciousness and language for stroke. Cerebral infarction often occurs in the middle cerebral artery, the proximal internal carotid artery and the basilar artery [6]. Since ischemia is a state of tissues or organs with temporary interruption of blood flow, restoring blood supply is one of the main therapeutic methods. However, reperfusion therapy potentially aggravates injury for too much free radical production and intracellular calcium overload which will both can induce the apoptosis of cells and cause ischemia–reperfusion (I/R) injury. Therefore, it is imperative to seek new therapeutic approaches.

Sphingosine 1-phosphate (S1P) is a sphingomyelin metabolite mainly derived from red blood cells (RBCs), platelets and endothelial cells (ECs). Besides action inside cells as a signaling molecule to regulate specific targets involved in fibroblasts, mitochondrial assembly and inflammation et al [7], S1P can be exported out of the cell acts as ligand of sphingosine 1-phosphate receptors (S1PRs) which was initially named as endothelial differentiation genes (EDGs) and plays a variety of biological functions such as angiogenesis and immune regulation [8]. Meanwhile, it also plays a crucial part in a variety of pathological conditions such as atherosclerosis, diabetes and cancer [9], [10]. In addition, the S1P signaling pathway interferes in ischemic damage of tissues or organs by controlling inflammation and cell apoptosis [11]. Activation of S1PR1 with specific agonists was reported to delay the development of atherosclerosis [12], [13]. Fingolimod (FTY720), an S1PRs non-specific agonist (except for S1PR2), was reported to inhibit the cardiomyocyte apoptosis on the ischemic border zone, thus reducing the infarction area in a porcine model of I/R [14]. Similarly, activation of S1PR1 with agonists could attenuate pulmonary I/R injury by reducing the expression of pro-inflammatory factors and neutrophil infiltration [15]. These results suggested the close relationship between S1P/S1PRs and atherosclerosis as well as ischemia, and may provide ideas for potential targets for the intervention of atherosclerosis and ischemia. This review focuses on the role of S1PRs in regulation of atherosclerosis and subsequent MI and ischemic stroke.

Section snippets

Atherosclerosis and ischemic diseases

Atherosclerosis is a chronic inflammatory disease based on lipid metabolism disorder and characterized by the formation of atherosclerotic plaques. Unhealthy lifestyle, genetic factors, aging, and disorders of the digestive and endocrine systems are all risk factors for atherosclerosis. In the early stage of atherosclerosis, LDL particles aggregates in the intima of the blood vessel and oxidizes to form oxidized LDL (ox-LDL). Monocytes circulating in the blood bind to chemokines and migrate to

S1P and its receptors

As a sphingomyelin metabolite, S1P plays an important role in cell proliferation, differentiation, apoptosis, angiogenesis, inflammation and other life processes [23]. Sphingomyelin is hydrolyzed by sphingomyelinase into ceramide (Cer), which then is converted by ceramidase to the precursor of S1P, Sphingosine (Sph). S1P is the product of Sph phosphorylation by sphingosine kinases 1 (Sphk1) and sphingosine kinases 2 (Sphk2). S1P in circulation is mainly derived from red blood cells (RBCs),

Anti-inflammatory and promoting vascular neointima formation of S1PR1

Feuerborn et al. [63] proved that raising S1P levels in LDL-R-/- mice exerted anti-atherogenic effects through favorable modulation of endothelial function. Moreover, hematopoietic S1P lyase deficiency mice presented an augment of S1P and suppressed the atherogenic response [64]. In addition, In the context of hypercholesterolemia, using Sphk1 inhibitor to lower endogenous plasma S1P leaded to pro-inflammatory and pro-atherogenic effects [65]. These results all demonstrated an atheroprotective

Improved role of S1PR1 in cardiac remodeling

Ahmed et al. [84] discovered that S1PR1, S1PR2 as well as S1PR3 were distributed in all chambers of the human and rat heart, hinting potential roles of S1PRs on a heart. Compared with the strong expression of S1PR1 and S1PR3 in heart, S1PR2 was in a lower expression, and there was no expression of S1PR4 and S1PR5 in heart. In fact, it was previously reported that the concentration of S1P in plasma was greatly reduced in patients with MI [85]. In a general way, S1PR1 acts as a protector in

Improvement of circulation by S1PR1 in ischemic brain

An in vivo study showed that S1PR1 selective agonists LASW1238 significantly reduced the area of cerebral infarction after the I/R of middle cerebral artery [98]. In a separate study, the researchers found that in mice with laser-induced cortical arteriole thrombosis, the selective S1PR1 modulators RP101075 changed the composition of thrombus via reducing the number of CD45+ cells in the thrombus, and reduced thrombus volume, thus improving post-thrombus microvascular circulation and

Perspective and conclusion

Given the roles in atherosclerosis and ischemia via regulating key segments such as inflammation of ECs, apoptosis and migration of macrophage, neointima formation and angiogenesis, S1PRs may serve as potential targets. For instance, Fingolimod (FTY720), was proved to reduce the size of atherosclerotic lesion in LDL-R−/− mice and Apo E−/− mice fed with a high-cholesterol diet [68]. Moreover, FTY720 has also been confirmed to ameliorate brain injury on ischemic stroke models via improving blood

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (Project 81770490) and the Specialized Research Fund for the Doctoral Program of Higher Education of China (20124324120005).

References (111)

  • S.E. Alvarez et al.

    Autocrine and paracrine roles of sphingosine-1-phosphate

    Trends Endocrinol. Metab.

    (2007)
  • M. Ksiazek

    Sources, metabolism, and regulation of circulating sphingosine-1-phosphate

    J. Lipid Res.

    (2015)
  • R. Feuerborn

    High density lipoprotein (HDL)-associated sphingosine 1-phosphate (S1P) inhibits macrophage apoptosis by stimulating STAT3 activity and survivin expression

    Atherosclerosis

    (2017)
  • H. Obinata

    Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice

    J. Lipid Res.

    (2019)
  • M. Kurano

    LDL receptor and ApoE are involved in the clearance of ApoM-associated sphingosine 1-phosphate

    J. Biol. Chem.

    (2015)
  • M. Kurano

    Liver involvement in sphingosine 1-phosphate dynamism revealed by adenoviral hepatic overexpression of apolipoprotein M

    Atherosclerosis

    (2013)
  • R.T. Windh

    Differential Coupling of the Sphingosine 1-Phosphate Receptors Edg-1, Edg-3, and H218/Edg-5 to the Gi, G q, and G12 Families of Heterotrimeric G Proteins

    J. Biol. Chem.

    (1999)
  • J. Du

    LPS and TNF-alpha induce expression of sphingosine-1-phosphate receptor-2 in human microvascular endothelial cells

    Pathol. Res. Pract.

    (2012)
  • A.J. MacLennan

    The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function

    Hear. Res.

    (2006)
  • D.R. Herr

    Sphingosine 1-phosphate receptors are essential mediators of eyelid closure during embryonic development

    J. Biol. Chem.

    (2013)
  • F. Potì

    SKI-II – a sphingosine kinase 1 inhibitor – exacerbates atherosclerosis in low-density lipoprotein receptor-deficient (LDL-R−/−) mice on high cholesterol diet

    Atherosclerosis

    (2015)
  • P. Holvoet et al.

    Angio-associated migratory cell protein and smooth muscle cell migration in development of restenosis and atherosclerosis

    J. Am. Coll. Cardiol.

    (2008)
  • T. Kitano

    Sphigosine-1-phosphate receptor 1 promotes neointimal hyperplasia in a mouse model of carotid artery injury

    Biochem. Biophys. Res. Commun.

    (2019)
  • D.Y. Lee

    Angiotensin II facilitates neointimal formation by increasing vascular smooth muscle cell migration: Involvement of APE/Ref-1-mediated overexpression of sphingosine-1-phosphate receptor 1

    Toxicol. Appl. Pharmacol.

    (2018)
  • W. Liu

    Sphingosine-1-phosphate receptor 2 mediates endothelial cells dysfunction by PI3K-Akt pathway under high glucose condition

    Eur. J. Pharmacol.

    (2016)
  • W. Zhang

    Sphingosine-1-phosphate receptor-2 mediated NFkappaB activation contributes to tumor necrosis factor-alpha induced VCAM-1 and ICAM-1 expression in endothelial cells

    Prostaglandins Other Lipid. Mediat.

    (2013)
  • T. Kimura

    Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells

    Cell Signal

    (2006)
  • S. Deng

    Exosomes from adipose-derived mesenchymal stem cells ameliorate cardiac damage after myocardial infarction by activating S1P/SK1/S1PR1 signaling and promoting macrophage M2 polarization

    Int. J. Biochem. Cell Biol.

    (2019)
  • D.P. Cormode

    Atherosclerotic plaque composition analysis with multicolor CT and targeted gold nanoparticles

    Radiology

    (2010)
  • J.M. Suarez-Rivero

    Atherosclerosis and coenzyme Q10

    Int. J. Mol. Sci.

    (2019)
  • W. Herrington

    Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease

    Circ. Res.

    (2016)
  • J. Palasubramaniam et al.

    Myocardial infarction-from atherosclerosis to thrombosis

    Arterioscler. Thromb. Vasc. Biol.

    (2019)
  • P. Dutta

    Myocardial infarction accelerates atherosclerosis

    Nature

    (2012)
  • J.S. Kim, L.R. Caplan, Clinical Stroke Syndromes, Front. Neurol. Neurosci, 40 (2016)...
  • A. Vestri

    Sphingosine 1-phosphate receptors: do they have a therapeutic potential in cardiac fibrosis?

    Front Pharmacol

    (2017)
  • M. Kurano, Y. Y, Sphingosine 1-Phosphate and Atherosclerosis, J. Atherosclerosis Thrombosis 25(1) (2018)...
  • Zohaib Raza, U. Saleem, Z. Naureen, Sphingosine 1-phosphate signaling in ischemia and reperfusion injury,...
  • L. Gonzalez

    Sphingosine-1-phosphate receptor 1, expressed in myeloid cells, slows diet-induced atherosclerosis and protects against macrophage apoptosis in Ldlr KO mice

    Int. J. Mol. Sci.

    (2017)
  • F. Poti

    KRP-203, sphingosine 1-phosphate receptor type 1 agonist, ameliorates atherosclerosis in LDL-R-/- mice

    Arterioscler Thromb. Vasc. Biol.

    (2013)
  • C.G. Santos-Gallego

    Sphingosine-1-phosphate receptor agonist fingolimod increases myocardial salvage and decreases adverse postinfarction left ventricular remodeling in a porcine model of ischemia/reperfusion

    Circulation

    (2016)
  • M.L. Stone

    Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury

    Am. J. Physiol. Lung Cell Mol. Physiol.

    (2015)
  • P. Libby

    Atherosclerosis

    Nat. Rev. Dis. Primers

    (2019)
  • Y. Zhu

    Research progress on the relationship between atherosclerosis and inflammation

    Biomolecules

    (2018)
  • J. Bejarano

    Nanoparticles for diagnosis and therapy of atherosclerosis and myocardial infarction: evolution toward prospective theranostic approaches

    Theranostics

    (2018)
  • H. Zhou

    Long noncoding RNAs in pathological cardiac remodeling: a review of the update literature

    Biomed. Res. Int.

    (2019)
  • T.V. Kirichenko

    Phytotherapy for the prevention of atherosclerosis-associated early cerebral ischemia

    Curr. Drug. Metab.

    (2018)
  • R.A. Grysiewicz, K. Thomas, D.K. Pandey, Epidemiology of ischemic and hemorrhagic stroke: incidence, prevalence,...
  • H. Obinata et al.

    Sphingosine 1-phosphate and inflammation

    Int. Immunol.

    (2019)
  • C. Bode

    Erythrocytes serve as a reservoir for cellular and extracellular sphingosine 1-phosphate

    J. Cell Biochem.

    (2010)
  • Y. Ono

    Sphingosine 1-phosphate release from platelets during clot formation close correlation between platelet count and serum sphingosine 1 phosphate concentration

    Lipids Health Dis.

    (2013)
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