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Emerging roles of sphingosylphosphorylcholine in modulating cardiovascular functions and diseases

Acta Pharmacologica Sinica (2018) | Download Citation



Sphingosylphosphorylcholine (SPC) is a bioactive sphingolipid in blood plasma that is metabolized from the hydrolysis of the membrane sphingolipid. SPC maintains low levels in the circulation under normal conditions, which makes studying its origin and action difficult. In recent years, however, it has been revealed that SPC may act as a first messenger through G protein-coupled receptors (S1P1-5, GPR12) or membrane lipid rafts, or as a second messenger mediating intracellular Ca2+ release in diverse human organ systems. SPC is a constituent of lipoproteins, and the activation of platelets promotes the release of SPC into blood, both implying a certain effect of SPC in modulating the pathological process of the heart and vessels. A line of evidence indeed confirms that SPC exerts a pronounced influence on the cardiovascular system through modulation of the functions of myocytes, vein endothelial cells, as well as vascular smooth muscle cells. In this review we summarize the current knowledge of the potential roles of SPC in the development of cardiovascular diseases and discuss the possible underlying mechanisms.

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  1. 1.

    Nixon GF, Mathieson FA, Hunter I. The multi-functional role of sphingosylphosphorylcholine. Prog Lipid Res. 2008;47:62–75.

  2. 2.

    Yatomi Y, Ruan F, Hakomori S, Igarashi Y. Sphingosine-1-phosphate: a platelet-activating sphingolipid released from agonist-stimulated human platelets. Blood. 1995;86:193–202.

  3. 3.

    Liliom K, Sun G, Bünemann M, Virág T, Nusser N, Baker DL, et al. Sphingosylphosphocholine is a naturally occurring lipid mediator in blood plasma: a possible role in regulating cardiac function via sphingolipid receptors. Biochem J. 2001;355:189–97.

  4. 4.

    Nofer JR, Levkau B, Wolinska I, Junker R, Fobker M, von Eckardstein A, et al. Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysosphingolipids. J Biol Chem. 2001;276:34480–5.

  5. 5.

    Kim KH, Kim YM, Lee MJ, Ko H-C, Kim M-B, Kim JH. Simvastatin inhibits sphingosylphosphorylcholine-induced differentiation of human mesenchymal stem cells into smooth muscle cells. Exp Mol Med. 2012;44:159–66.

  6. 6.

    Yamamoto H, Naito Y, Okano M, Kanazawa T, Takematsu H, Kozutsumi Y. Sphingosylphosphorylcholine and lysosulfatide have inverse regulatory functions in monocytic cell differentiation into macrophages. Arch Biochem Biophys. 2011;506:83–91.

  7. 7.

    Jeon ES, Song HY, Kim MR, Moon HJ, Bae YC, Jung JS, et al. Sphingosylphosphorylcholine induces proliferation of human adipose tissue-derived mesenchymal stem cells via activation of JNK. J Lipid Res. 2006;47:653–64.

  8. 8.

    Jeon ES, Lee MJ, Sung S-M, Kim JH. Sphingosylphosphorylcholine induces apoptosis of endothelial cells through reactive oxygen species-mediated activation of ERK. J Cell Biochem. 2007;100:1536–47.

  9. 9.

    Kurek K, Piotrowska DM, Wiesiolek-Kurek P, Chabowska A, Lukaszuk B, Zendzian-Piotrowska M. The role of sphingolipids in selected cardiovascular diseases. Post Hig Med Dosw. 2013;67:1018–26.

  10. 10.

    Knapp M. Cardioprotective role of sphingosine-1-phosphate. J Physiol Pharmacol. 2011;62:601–7.

  11. 11.

    Kurokawa T, Yumiya Y, Fujisawa H, Shirao S, Kashiwagi S, Sato M, et al. Elevated concentrations of sphingosylphosphorylcholine in cerebrospinal fluid after subarachnoid hemorrhage: a possible role as a spasmogen. J Clin Neurosci. 2009;16:1064–8.

  12. 12.

    Hara J, Higuchi K, Okamoto R, Kawashima M, Imokawa G. High-expression of sphingomyelin deacylase is an important determinant of ceramide deficiency leading to barrier disruption in atopic dermatitis. J Invest Dermatol. 2000;115:406–13.

  13. 13.

    Xu Y, Gaudette DC, Boynton JD, Frankel A, Fang XJ, Sharma A, et al. Characterization of an ovarian cancer activating factor in ascites from ovarian cancer patients. Clin Cancer Res. 1995;1:1223–32.

  14. 14.

    Betto R, Teresi A, Turcato F, Salviati G, Sabbadini RA, Krown K, et al. Sphingosylphosphocholine modulates the ryanodine receptor/calcium-release channel of cardiac sarcoplasmic reticulum membranes. Biochem J. 1997;322:327–33.

  15. 15.

    Uehara A, Yasukochi M, Imanaga I, Berlin JR. Effect of sphingosylphosphorylcholine on the single channel gating properties of the cardiac ryanodine receptor. FEBS Lett. 1999;460:467–71.

  16. 16.

    Yasukochi M, Uehara A, Kobayashi S, Berlin JR. Ca2+ and voltage dependence of cardiac ryanodine receptor channel block by sphingosylphosphorylcholine. Pflug Arch. 2003;445:665–73.

  17. 17.

    Kovacs E, Liliom K. Sphingosylphosphorylcholine as a novel calmodulin inhibitor. Biochem J. 2008;410:427–37.

  18. 18.

    Kovacs E, Toth J, Vertessy BG, Liliom K. Dissociation of calmodulin-target peptide complexes by the lipid mediator sphingosylphosphorylcholine: implications in calcium signaling. J Biol Chem. 2010;285:1799–808.

  19. 19.

    Kovacs E, Harmat V, Toth J, Vertessy BG, Modos K, Kardos J, et al. Structure and mechanism of calmodulin binding to a signaling sphingolipid reveal new aspects of lipid-protein interactions. FASEB J. 2010;24:3829–39.

  20. 20.

    Kovacs E, Xu L, Pasek DA, Liliom K, Meissner G. Regulation of ryanodine receptors by sphingosylphosphorylcholine: involvement of both calmodulin-dependent and -independent mechanisms. Biochem Biophys Res Commun. 2010;401:281–6.

  21. 21.

    Scherer M, Boettcher A, Schmitz G, Liebisch G. Sphingolipid profiling of human plasma and FPLC-separated lipoprotein fractions by hydrophilic interaction chromatography tandem mass spectrometry. Biochim Biophys Acta. 2011;1811:68–75.

  22. 22.

    Alewijnse AE, Peters SLM, Michel MC. Cardiovascular effects of sphingosine-1-phosphate and other sphingomyelin metabolites. Br J Pharmacol. 2004;143:666–84.

  23. 23.

    Lee HY, Lee SY, Kim SD, Shim JW, Kim HJ, Jung YS, et al. Sphingosylphosphorylcholine stimulates CCL2 production from human umbilical vein endothelial cells. J Immunol. 2011;186:4347–53.

  24. 24.

    Jeon ES, Moon HJ, Lee MJ, Song HY, Kim YM, Bae YC, et al. Sphingosylphosphorylcholine induces differentiation of human mesenchymal stem cells into smooth-muscle-like cells through a TGF-beta-dependent mechanism. J Cell Sci. 2006;119:4994–5005.

  25. 25.

    Meyer zu Heringdorf D, Himmel HM, Jakobs KH. Sphingosylphosphorylcholine-biological functions and mechanisms of action. Biochim Biophys Acta. 2002;1582:178–89.

  26. 26.

    Okajima F, Kondo Y. Pertussis toxin inhibits phospholipase C activation and Ca2+ mobilization by sphingosylphosphorylcholine and galactosylsphingosine in HL60 leukemia cells. Implications of GTP-binding protein-coupled receptors for lysosphingolipids. J Biol Chem. 1995;270:26332–40.

  27. 27.

    Chin TY, Chueh SH. Sphingosylphosphorylcholine stimulates mitogen-activated protein kinase via a Ca2+-dependent pathway. Am J Physiol. 1998;275:C1255–63.

  28. 28.

    Lyons JM, Karin NJ. A role for G protein-coupled lysophospholipid receptors in sphingolipid-induced Ca2+signaling in MC3T3-E1 osteoblastic cells. J Bone Miner Res. 2001;16:2035–42.

  29. 29.

    Meyer zu Heringdorf D, Jakobs KH. Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. Biochim Biophys Acta. 2007;1768:923–40.

  30. 30.

    Okamoto H, Takuwa N, Gonda K, Okazaki H, Chang K, Yatomi Y, et al. EDG1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signaling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition. J Biol Chem. 1998;273:27104–10.

  31. 31.

    Okamoto H, Takuwa N, Yatomi Y, Gonda K, Shigematsu H, Takuwa Y. EDG3 is a functional receptor specific for sphingosine 1-phosphate and sphingosylphosphorylcholine with signaling characteristics distinct from EDG1 and AGR16. Biochem Biophys Res Commun. 1999;260:203–8.

  32. 32.

    Ancellin N, Hla T. Differential pharmacological properties and signal transduction of the sphingosine 1-phosphate receptors EDG-1, EDG-3, and EDG-5. J Biol Chem. 1999;274:18997–9002.

  33. 33.

    Windh RT, Lee MJ, Hla T, An S, Barr AJ, Manning DR. Differential coupling of the sphingosine 1-phosphate receptors Edg-1, Edg-3, and H218/Edg-5 to the G(i), G(q), and G(12) families of heterotrimeric G proteins. J Biol Chem. 1999;274:27351–8.

  34. 34.

    Wang J-Q, Kon J, Mogi C, Tobo M, Damirin A, Sato K, et al. TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor. J Biol Chem. 2004;279:45626–33.

  35. 35.

    Ignatov A, Lintzel J, Hermans-Borgmeyer I, Kreienkamp H-J, Joost P, Thomsen S, et al. Role of the G-protein-coupled receptor GPR12 as high-affinity receptor for sphingosylphosphorylcholine and its expression and function in brain development. J Neurosci. 2003;23:907–14.

  36. 36.

    Morikage N, Kishi H, Sato M, Guo F, Shirao S, Yano T, et al. Cholesterol primes vascular smooth muscle to induce Ca2 sensitization mediated by a sphingosylphosphorylcholine-Rho-kinase pathway: possible role for membrane raft. Circ Res. 2006;99:299–306.

  37. 37.

    Suzuki KGN. Lipid rafts generate digital-like signal transduction in cell plasma membranes. Biotechnol J. 2012;7:753–61.

  38. 38.

    Head BP, Patel HH, Insel PA. Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim Biophys Acta. 2014;1838:532–45.

  39. 39.

    Herzog C, Schmitz M, Levkau B, Herrgott I, Mersmann J, Larmann J, et al. Intravenous sphingosylphosphorylcholine protects ischemic and postischemic myocardial tissue in a mouse model of myocardial ischemia/reperfusion injury. Mediat Inflamm. 2010;2010:425191.

  40. 40.

    Boguslawski G, Lyons D, Harvey KA, Kovala AT, English D. Sphingosylphosphorylcholine induces endothelial cell migration and morphogenesis. Biochem Biophys Res Commun. 2000;272:603–9.

  41. 41.

    Schmidt A, Geigenmüller S, Buddecke E. The antiatherogenic and antiinflammatory effect of HDL-associated lysosphingolipids operates via Akt—NF-kappaB signalling pathways in human vascular endothelial cells. Basic Res Cardiol. 2006;45:109–16.

  42. 42.

    Liliom K, Bunemann M, Sun G, Miller D, Desiderio DM, Brandts B, et al. Sphingosylphosphorylcholine is a bona fide mediator regulating heart rate. Ann N Y Acad Sci. 2000;905:308–10.

  43. 43.

    Himmel HM, Meyer Zu Heringdorf D, Graf E, Dobrev D, Kortner A, Schuler S, et al. Evidence for Edg-3 receptor-mediated activation of I(K.ACh) by sphingosine-1-phosphate in human atrial cardiomyocytes. Mol Pharmacol. 2000;58:449–54.

  44. 44.

    Yasui K, Palade P. Sphingolipid actions on sodium and calcium currents of rat ventricular myocytes. Am J Physiol. 1996;270:C645–9.

  45. 45.

    Robert P, Tsui P, Laville MP, Livi GP, Sarau HM, Bril A, et al. EDG1 receptor stimulation leads to cardiac hypertrophy in rat neonatal myocytes. J Mol Cell Cardiol. 2001;33:1589–606.

  46. 46.

    Yue H-W, Liu J, Liu P-P, Li W-J, Chang F, Miao J-Y, et al. Sphingosylphosphorylcholine protects cardiomyocytes against ischemic apoptosis via lipid raft/PTEN/Akt1/mTOR mediated autophagy. Biochim Biophys Acta. 2015;1851:1186–93.

  47. 47.

    Todoroki-Ikeda N, Mizukami Y, Mogami K, Kusuda T, Yamamoto K, Miyake T, et al. Sphingosylphosphorylcholine induces Ca(2+)-sensitization of vascular smooth muscle contraction: possible involvement of rho-kinase. FEBS Lett. 2000;482:85–90.

  48. 48.

    Nakao F, Kobayashi S, Mogami K, Mizukami Y, Shirao S, Miwa S, et al. Involvement of Src family protein tyrosine kinases in Ca(2+) sensitization of coronary artery contraction mediated by a sphingosylphosphorylcholine-Rho-kinase pathway. Circ Res. 2002;91:953–60.

  49. 49.

    Shirao S, Kashiwagi S, Sato M, Miwa S, Nakao F, Kurokawa T, et al. Sphingosylphosphorylcholine is a novel messenger for Rho-kinase-mediated Ca2+ sensitization in the bovine cerebral artery: unimportant role for protein kinase C. Circ Res. 2002;91:112–9.

  50. 50.

    Somlyo AV. New roads leading to Ca2+ sensitization. Circ Res. 2002;91:83–4.

  51. 51.

    Ge D, Jing Q, Meng N, Su L, Zhang Y, Zhang S, et al. Regulation of apoptosis and autophagy by sphingosylphosphorylcholine in vascular endothelial cells. J Cell Physiol. 2011;226:2827–33.

  52. 52.

    Piao Y-J, Lee C-H, Zhu MJ, Kye K-C, Kim J-M, Seo Y-J, et al. Involvement of urokinase-type plasminogen activator in sphingosylphosphorylcholine-induced angiogenesis. Exp Dermatol. 2005;14:356–62.

  53. 53.

    Kim K-S, Ren J, Jiang Y, Ebrahem Q, Tipps R, Cristina K, et al. GPR4 plays a critical role in endothelial cell function and mediates the effects of sphingosylphosphorylcholine. FASEB J. 2005;19:819–21.

  54. 54.

    Mogami K, Mizukami Y, Todoroki-Ikeda N, Ohmura M, Yoshida K, Miwa S, et al. Sphingosylphosphorylcholine induces cytosolic Ca(2+) elevation in endothelial cells in situ and causes endothelium-dependent relaxation through nitric oxide production in bovine coronary artery. FEBS Lett. 1999;457:375–80.

  55. 55.

    Ge D, Meng N, Su L, Zhang Y, Zhang S-l, Miao J-y, et al. Human vascular endothelial cells reduce sphingosylphosphorylcholine-induced smooth muscle cell contraction in co-culture system through integrin beta 4 and Fyn. Acta Pharmacol Sin. 2012;33:57–65.

  56. 56.

    Boguslawski G, Grogg JR, Welch Z, Ciechanowicz S, Sliva D, Kovala AT, et al. Migration of vascular smooth muscle cells induced by sphingosine 1-phosphate and related lipids: potential role in the angiogenic response. Exp Cell Res. 2002;274:264–74.

  57. 57.

    Mathieson FA, Nixon GF. Sphingolipids differentially regulate mitogen-activated protein kinases and intracellular Ca2+ in vascular smooth muscle: effects on CREB activation. Br J Pharmacol. 2006;147:351–9.

  58. 58.

    Wirrig C, Hunter I, Mathieson FA, Nixon GF. Sphingosylphosphorylcholine is a proinflammatory mediator in cerebral arteries. J Cereb Blood Flow Metab. 2011;31:212–21.

  59. 59.

    Jeon ES, Park WS, Lee MJ, Kim YM, Han J, Kim JH. A Rho kinase/myocardin-related transcription factor-A-dependent mechanism underlies the sphingosylphosphorylcholine-induced differentiation of mesenchymal stem cells into contractile smooth muscle cells. Circ Res. 2008;103:635–42.

  60. 60.

    Kleger A, Liebau S, Lin Q, von Wichert G, Seufferlein T. The impact of bioactive lipids on cardiovascular development. Stem Cells Int. 2011;2011:916180.

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This work was financially supported by the National Science Foundation of China (31501122; 31371158; 31671180; 31070999; 81570454), Science and Technology Developmental Project of Shandong Province (2016GSF201035 and ZR2014CM030), and Shandong Excellent Young Scientist Award Fund (BS2014SW031).

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  1. These authors contributed equally: Di Ge, Hong-wei Yue.


  1. School of Biological Science and Technology, University of Jinan, Jinan, 250022, China

    • Di Ge
  2. Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, 250022, China

    • Di Ge
    • , Hong-wei Yue
    • , Hong-hong Liu
    •  & Jing Zhao


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Correspondence to Di Ge or Jing Zhao.

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