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Sphingolipid Metabolism and Signaling in Endothelial Cell Functions

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Sphingolipid Metabolism and Metabolic Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1372))

Abstract

The endothelium, inner layer of blood vessels, constitutes a metabolically active paracrine, endocrine, and autocrine organ, able to sense the neighboring environment and exert a variety of biological functions important to preserve the health of vasculature, tissues, and organs. Sphingolipids are both fundamental structural components of the eukaryotic membranes and signaling molecules regulating a variety of biological functions. Ceramide and sphingosine-1-phosphate (S1P), bioactive sphingolipids, have emerged as important regulators of cardiovascular functions in health and disease. In this review we discuss recent insights into the role of ceramide and S1P biosynthesis and signaling in regulating endothelial cell functions, in health and diseases. We also highlight advances into the mechanisms regulating serine palmitoyltransferase, the first and rate-limiting enzyme of de novo sphingolipid biosynthesis, with an emphasis on its inhibitors, ORMDL and NOGO-B. Understanding the molecular mechanisms regulating the sphingolipid de novo biosynthesis may provide the foundation for therapeutic modulation of this pathway in a variety of conditions, including cardiovascular diseases, associated with derangement of this pathway.

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References

  1. Bazzoni, G., & Dejana, E. (2004). Endothelial cell-to-cell junctions: Molecular organization and role in vascular homeostasis. Physiological Reviews, 84, 869–901.

    Article  CAS  PubMed  Google Scholar 

  2. Aird, W. C. (2007). Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circulation Research, 100, 158–173.

    Article  CAS  PubMed  Google Scholar 

  3. Poisson, J., et al. (2017). Liver sinusoidal endothelial cells: Physiology and role in liver diseases. Journal of Hepatology, 66, 212–227.

    Article  CAS  PubMed  Google Scholar 

  4. Tse, D., & Stan, R. V. (2010). Morphological heterogeneity of endothelium. Seminars in Thrombosis and Hemostasis, 36, 236–245.

    Article  CAS  PubMed  Google Scholar 

  5. Pober, J. S., & Sessa, W. C. (2014). Inflammation and the blood microvascular system. Cold Spring Harbor Perspectives in Biology, 7, a016345.

    Article  PubMed  Google Scholar 

  6. van Hinsbergh, V. W. (2012). Endothelium—role in regulation of coagulation and inflammation. Seminars in Immunopathology, 34, 93–106.

    Article  PubMed  CAS  Google Scholar 

  7. Arnout, J., Hoylaerts, M. F., & Lijnen, H. R. (2006). Haemostasis. In Handbook of experimental pharmacology (pp. 1–41).

    Google Scholar 

  8. Furchgott, R. F., & Zawadzki, J. V. (1980). The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature, 288, 373–376.

    Article  CAS  PubMed  Google Scholar 

  9. Ignarro, L. J., Byrns, R. E., Buga, G. M., & Wood, K. S. (1987). Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical. Circulation Research, 61, 866–879.

    Article  CAS  PubMed  Google Scholar 

  10. Palmer, R. M., Ferrige, A. G., & Moncada, S. (1987). Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature, 327, 524–526.

    Article  CAS  PubMed  Google Scholar 

  11. Arnold, W. P., Mittal, C. K., Katsuki, S., & Murad, F. (1977). Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. Proceedings of the National Academy of Sciences of the United States of America, 74, 3203–3207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rapoport, R. M., & Murad, F. (1983). Agonist-induced endothelium-dependent relaxation in rat thoracic aorta may be mediated through cGMP. Circulation Research, 52, 352–357.

    Article  CAS  PubMed  Google Scholar 

  13. Parton, R. G., & del Pozo, M. A. (2013). Caveolae as plasma membrane sensors, protectors and organizers. Nature Reviews. Molecular Cell Biology, 14, 98–112.

    Article  CAS  PubMed  Google Scholar 

  14. Forstermann, U., & Sessa, W. C. (2012). Nitric oxide synthases: Regulation and function. European Heart Journal, 33(829–837), 837a–837d.

    Google Scholar 

  15. Fulton, D., et al. (1999). Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature, 399, 597–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dimmeler, S., et al. (1999). Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature, 399, 601–605.

    Article  CAS  PubMed  Google Scholar 

  17. Vanhoutte, P. M., Zhao, Y., Xu, A., & Leung, S. W. (2016). Thirty years of saying NO: Sources, fate, actions, and misfortunes of the endothelium-derived vasodilator mediator. Circulation Research, 119, 375–396.

    Article  CAS  PubMed  Google Scholar 

  18. Harrison, D. G., Freiman, P. C., Armstrong, M. L., Marcus, M. L., & Heistad, D. D. (1987). Alterations of vascular reactivity in atherosclerosis. Circulation Research, 61, 1174–1180.

    Article  Google Scholar 

  19. Panza, J. A., Quyyumi, A. A., Brush, J. E., Jr., & Epstein, S. E. (1990). Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. The New England Journal of Medicine, 323, 22–27.

    Article  CAS  PubMed  Google Scholar 

  20. Taddei, S., et al. (1996). Defective L-arginine-nitric oxide pathway in offspring of essential hypertensive patients. Circulation, 94, 1298–1303.

    Article  CAS  PubMed  Google Scholar 

  21. Celermajer, D. S., et al. (1992). Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet, 340, 1111–1115.

    Article  CAS  PubMed  Google Scholar 

  22. Balletshofer, B. M., et al. (2000). Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation, 101, 1780–1784.

    Article  CAS  PubMed  Google Scholar 

  23. Merrill, A. H., Jr., & Wang, E. (1986). Biosynthesis of long-chain (sphingoid) bases from serine by LM cells. Evidence for introduction of the 4-trans-double bond after de novo biosynthesis of N-acylsphinganine(s). The Journal of Biological Chemistry, 261, 3764–3769.

    Article  CAS  PubMed  Google Scholar 

  24. Pewzner-Jung, Y., Ben-Dor, S., & Futerman, A. H. (2006). When do lasses (longevity assurance genes) become CerS (ceramide synthases)?: Insights into the regulation of ceramide synthesis. The Journal of Biological Chemistry, 281, 25001–25005.

    Article  CAS  PubMed  Google Scholar 

  25. Michel, C., et al. (1997). Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. The Journal of Biological Chemistry, 272, 22432–22437.

    Article  CAS  PubMed  Google Scholar 

  26. Gault, C. R., Obeid, L. M., & Hannun, Y. A. (2010). An overview of sphingolipid metabolism: From synthesis to breakdown. Advances in Experimental Medicine and Biology, 688, 1–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hanada, K., et al. (2003). Molecular machinery for non-vesicular trafficking of ceramide. Nature, 426, 803–809.

    Article  CAS  PubMed  Google Scholar 

  28. Watson, P., & Stephens, D. J. (2005). ER-to-Golgi transport: Form and formation of vesicular and tubular carriers. Biochimica et Biophysica Acta, 1744, 304–315.

    Article  CAS  PubMed  Google Scholar 

  29. Sugiura, M., et al. (2002). Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization. The Journal of Biological Chemistry, 277, 23294–23300.

    Article  CAS  PubMed  Google Scholar 

  30. Mao, C., & Obeid, L. M. (2008). Ceramidases: Regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochimica et Biophysica Acta, 1781, 424–434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wattenberg, B. W., Pitson, S. M., & Raben, D. M. (2006). The sphingosine and diacylglycerol kinase superfamily of signaling kinases: Localization as a key to signaling function. Journal of Lipid Research, 47, 1128–1139.

    Article  CAS  PubMed  Google Scholar 

  32. Ikeda, M., Kihara, A., & Igarashi, Y. (2004). Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5′-phosphate binding domain exposed to the cytosol. Biochemical and Biophysical Research Communications, 325, 338–343.

    Article  CAS  PubMed  Google Scholar 

  33. van Meer, G., Voelker, D. R., & Feigenson, G. W. (2008). Membrane lipids: Where they are and how they behave. Nature Reviews. Molecular Cell Biology, 9, 112–124.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Kolesnick, R. N., Goni, F. M., & Alonso, A. (2000). Compartmentalization of ceramide signaling: Physical foundations and biological effects. Journal of Cellular Physiology, 184, 285–300.

    Article  CAS  PubMed  Google Scholar 

  35. Lingwood, D., & Simons, K. (2010). Lipid rafts as a membrane-organizing principle. Science, 327, 46–50.

    Article  CAS  PubMed  Google Scholar 

  36. Pike, L. J. (2006). Rafts defined: A report on the keystone symposium on lipid rafts and cell function. Journal of Lipid Research, 47, 1597–1598.

    Article  CAS  PubMed  Google Scholar 

  37. Rietveld, A., & Simons, K. (1998). The differential miscibility of lipids as the basis for the formation of functional membrane rafts. Biochimica et Biophysica Acta, 1376, 467–479.

    Article  CAS  PubMed  Google Scholar 

  38. Simons, K., & Ikonen, E. (1997). Functional rafts in cell membranes. Nature, 387, 569–572.

    Article  CAS  PubMed  Google Scholar 

  39. Nyholm, T. K. (2015). Lipid-protein interplay and lateral organization in biomembranes. Chemistry and Physics of Lipids, 189, 48–55.

    Article  CAS  PubMed  Google Scholar 

  40. Bollinger, C. R., Teichgraber, V., & Gulbins, E. (2005). Ceramide-enriched membrane domains. Biochimica et Biophysica Acta, 1746, 284–294.

    Article  CAS  PubMed  Google Scholar 

  41. Insel, P. A., et al. (2005). Compartmentation of G-protein-coupled receptors and their signalling components in lipid rafts and caveolae. Biochemical Society Transactions, 33, 1131–1134.

    Article  CAS  PubMed  Google Scholar 

  42. Pike, L. J. (2005). Growth factor receptors, lipid rafts and caveolae: An evolving story. Biochimica et Biophysica Acta, 1746, 260–273.

    Article  CAS  PubMed  Google Scholar 

  43. Lippincott-Schwartz, J., & Phair, R. D. (2010). Lipids and cholesterol as regulators of traffic in the endomembrane system. Annual Review of Biophysics, 39, 559–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hannun, Y. A., & Obeid, L. M. (2008). Principles of bioactive lipid signalling: Lessons from sphingolipids. Nature Reviews. Molecular Cell Biology, 9, 139–150.

    Article  CAS  PubMed  Google Scholar 

  45. Siddique, M. M., Li, Y., Chaurasia, B., Kaddai, V. A., & Summers, S. A. (2015). Dihydroceramides: From bit players to Lead actors. The Journal of Biological Chemistry, 290, 15371–15379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Presa, N., Gomez-Larrauri, A., Dominguez-Herrera, A., Trueba, M., & Gomez-Munoz, A. (2020). Novel signaling aspects of ceramide 1-phosphate. Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids, 1865, 158630.

    Article  CAS  PubMed  Google Scholar 

  47. Spiegel, S., & Milstien, S. (2003). Sphingosine-1-phosphate: An enigmatic signalling lipid. Nature Reviews. Molecular Cell Biology, 4, 397–407.

    Article  CAS  PubMed  Google Scholar 

  48. Chalfant, C. E., et al. (1999). Long chain ceramides activate protein phosphatase-1 and protein phosphatase-2A. Activation is stereospecific and regulated by phosphatidic acid. The Journal of Biological Chemistry, 274, 20313–20317.

    Article  CAS  PubMed  Google Scholar 

  49. Dobrowsky, R. T., Kamibayashi, C., Mumby, M. C., & Hannun, Y. A. (1993). Ceramide activates heterotrimeric protein phosphatase 2A. The Journal of Biological Chemistry, 268, 15523–15530.

    Article  CAS  PubMed  Google Scholar 

  50. Lozano, J., et al. (1994). Protein kinase C zeta isoform is critical for kappa B-dependent promoter activation by sphingomyelinase. The Journal of Biological Chemistry, 269, 19200–19202.

    Article  CAS  PubMed  Google Scholar 

  51. Xiong, Y., Yang, P., Proia, R. L., & Hla, T. (2014). Erythrocyte-derived sphingosine 1-phosphate is essential for vascular development. The Journal of Clinical Investigation, 124, 4823–4828.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hanel, P., Andreani, P., & Graler, M. H. (2007). Erythrocytes store and release sphingosine 1-phosphate in blood. FASEB Journal, 21, 1202–1209.

    Article  PubMed  CAS  Google Scholar 

  53. Cantalupo, A., et al. (2015). Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure. Nature Medicine, 21, 1028–1037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Del Gaudio, I., et al. (2021). Endothelial Spns2 and ApoM regulation of vascular tone and hypertension via Sphingosine-1-phosphate. Journal of the American Heart Association, 10, e021261.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Venkataraman, K., et al. (2008). Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circulation Research, 102, 669–676.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pappu, R., et al. (2007). Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science, 316, 295–298.

    Article  CAS  PubMed  Google Scholar 

  57. Fukuhara, S., et al. (2012). The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice. The Journal of Clinical Investigation, 122, 1416–1426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hisano, Y., Kobayashi, N., Yamaguchi, A., & Nishi, T. (2012). Mouse SPNS2 functions as a sphingosine-1-phosphate transporter in vascular endothelial cells. PLoS One, 7, e38941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hla, T., Venkataraman, K., & Michaud, J. (2008). The vascular S1P gradient-cellular sources and biological significance. Biochimica et Biophysica Acta, 1781, 477–482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Schwab, S. R., et al. (2005). Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science, 309, 1735–1739.

    Article  CAS  PubMed  Google Scholar 

  61. Matloubian, M., et al. (2004). Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature, 427, 355–360.

    Article  CAS  PubMed  Google Scholar 

  62. Pham, T. H., Okada, T., Matloubian, M., Lo, C. G., & Cyster, J. G. (2008). S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress. Immunity, 28, 122–133.

    Article  CAS  PubMed  Google Scholar 

  63. Lo, C. G., Xu, Y., Proia, R. L., & Cyster, J. G. (2005). Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. The Journal of Experimental Medicine, 201, 291–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Murata, N., et al. (2000). Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. The Biochemical Journal, 352(Pt 3), 809–815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sevvana, M., et al. (2009). Serendipitous fatty acid binding reveals the structural determinants for ligand recognition in apolipoprotein M. Journal of Molecular Biology, 393, 920–936.

    Article  CAS  PubMed  Google Scholar 

  66. Christoffersen, C., et al. (2011). Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. Proceedings of the National Academy of Sciences of the United States of America, 108, 9613–9618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kumaraswamy, S. B., Linder, A., Akesson, P., & Dahlback, B. (2012). Decreased plasma concentrations of apolipoprotein M in sepsis and systemic inflammatory response syndromes. Critical Care, 16, R60.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Frej, C., et al. (2016). Sphingosine 1-phosphate and its carrier apolipoprotein M in human sepsis and in Escherichia coli sepsis in baboons. Journal of Cellular and Molecular Medicine, 20(6), 1170–1181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sattler, K. J., et al. (2010). Sphingosine 1-phosphate levels in plasma and HDL are altered in coronary artery disease. Basic Research in Cardiology, 105, 821–832.

    Article  CAS  PubMed  Google Scholar 

  70. Argraves, K. M., et al. (2011). S1P, dihydro-S1P and C24:1-ceramide levels in the HDL-containing fraction of serum inversely correlate with occurrence of ischemic heart disease. Lipids in Health and Disease, 10, 70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gomaraschi, M., et al. (2013). Inflammation impairs eNOS activation by HDL in patients with acute coronary syndrome. Cardiovascular Research, 100, 36–43.

    Article  CAS  PubMed  Google Scholar 

  72. Sattler, K., et al. (2014). HDL-bound sphingosine 1-phosphate (S1P) predicts the severity of coronary artery atherosclerosis. Cellular Physiology and Biochemistry, 34, 172–184.

    Article  CAS  PubMed  Google Scholar 

  73. Jiao, G. Q., et al. (2007). A prospective evaluation of apolipoprotein M gene T-778C polymorphism in relation to coronary artery disease in Han Chinese. Clinical Biochemistry, 40, 1108–1112.

    Article  CAS  PubMed  Google Scholar 

  74. Xu, W. W., et al. (2008). A genetic variant of apolipoprotein M increases susceptibility to coronary artery disease in a Chinese population. Clinical and Experimental Pharmacology & Physiology, 35, 546–551.

    Article  CAS  Google Scholar 

  75. Claesson-Welsh, L., Dejana, E., & McDonald, D. M. (2021). Permeability of the endothelial barrier: Identifying and reconciling controversies. Trends in Molecular Medicine, 27, 314–331.

    Article  CAS  PubMed  Google Scholar 

  76. Mehta, D., Ravindran, K., & Kuebler, W. M. (2014). Novel regulators of endothelial barrier function. American Journal of Physiology. Lung Cellular and Molecular Physiology, 307, L924–L935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Giannotta, M., Trani, M., & Dejana, E. (2013). VE-cadherin and endothelial adherens junctions: Active guardians of vascular integrity. Developmental Cell, 26, 441–454.

    Article  CAS  PubMed  Google Scholar 

  78. Hartsock, A., & Nelson, W. J. (2008). Adherens and tight junctions: Structure, function and connections to the actin cytoskeleton. Biochimica et Biophysica Acta, 1778, 660–669.

    Article  CAS  PubMed  Google Scholar 

  79. Lee, M. J., et al. (1999). Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell, 99, 301–312.

    Article  CAS  PubMed  Google Scholar 

  80. Garcia, J. G., et al. (2001). Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. The Journal of Clinical Investigation, 108, 689–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Xiong, Y., & Hla, T. (2014). S1P control of endothelial integrity. Current Topics in Microbiology and Immunology, 378, 85–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Burg, N., Swendeman, S., Worgall, S., Hla, T., & Salmon, J. E. (2018). Sphingosine 1-phosphate receptor 1 signaling maintains endothelial cell barrier function and protects against immune complex-induced vascular injury. Arthritis & Rhematology, 70, 1879–1889.

    Article  CAS  Google Scholar 

  83. Akhter, M. Z., et al. (2021). Programming to S1PR1(+) endothelial cells promotes restoration of vascular integrity. Circulation Research, 129, 221–236.

    Article  CAS  PubMed  Google Scholar 

  84. Tauseef, M., et al. (2008). Activation of sphingosine kinase-1 reverses the increase in lung vascular permeability through sphingosine-1-phosphate receptor signaling in endothelial cells. Circulation Research, 103, 1164–1172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Camerer, E., et al. (2009). Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice. Journal of Clinical Investigation, 119(7), 1871–1879.

    CAS  Google Scholar 

  86. Schaphorst, K. L., et al. (2003). Role of sphingosine-1 phosphate in the enhancement of endothelial barrier integrity by platelet-released products. American Journal of Physiology. Lung Cellular and Molecular Physiology, 285, L258–L267.

    Article  CAS  PubMed  Google Scholar 

  87. Gazit, S. L., et al. (2016). Platelet and erythrocyte sources of S1P are redundant for vascular development and homeostasis, but both rendered essential after plasma S1P depletion in anaphylactic shock. Circulation Research, 119, e110–e126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Herzog, B. H., et al. (2013). Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature, 502, 105–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Jeya Paul, J., et al. (2020). Inflammatory conditions disrupt constitutive endothelial cell barrier stabilization by alleviating autonomous secretion of sphingosine 1-phosphate. Cell, 9, 928.

    Article  CAS  Google Scholar 

  90. Simmons, S., et al. (2019). High-endothelial cell-derived S1P regulates dendritic cell localization and vascular integrity in the lymph node. eLife, 8, e41239.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Christensen, P. M., et al. (2016). Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1. FASEB Journal, 30(6), 2351–2359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jernigan, P. L., Makley, A. T., Hoehn, R. S., Edwards, M. J., & Pritts, T. A. (2015). The role of sphingolipids in endothelial barrier function. Biological Chemistry, 396, 681–691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Maceyka, M., & Spiegel, S. (2014). Sphingolipid metabolites in inflammatory disease. Nature, 510, 58–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Goggel, R., et al. (2004). PAF-mediated pulmonary edema: A new role for acid sphingomyelinase and ceramide. Nature Medicine, 10, 155–160.

    Article  PubMed  CAS  Google Scholar 

  95. Wong, M. L., et al. (2000). Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: A possible link between inflammatory cytokines and atherogenesis. Proceedings of the National Academy of Sciences of the United States of America, 97, 8681–8686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Claus, R. A., et al. (2005). Role of increased sphingomyelinase activity in apoptosis and organ failure of patients with severe sepsis. FASEB Journal, 19, 1719–1721.

    Article  CAS  PubMed  Google Scholar 

  97. Lindner, K., Uhlig, U., & Uhlig, S. (2005). Ceramide alters endothelial cell permeability by a nonapoptotic mechanism. British Journal of Pharmacology, 145, 132–140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Schweitzer, K. S., et al. (2011). Mechanisms of lung endothelial barrier disruption induced by cigarette smoke: Role of oxidative stress and ceramides. American Journal of Physiology. Lung Cellular and Molecular Physiology, 301, L836–L846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Li, H., et al. (2002). Dual effect of ceramide on human endothelial cells: Induction of oxidative stress and transcriptional upregulation of endothelial nitric oxide synthase. Circulation, 106, 2250–2256.

    Article  CAS  PubMed  Google Scholar 

  100. Zeidan, Y. H., Jenkins, R. W., & Hannun, Y. A. (2008). Remodeling of cellular cytoskeleton by the acid sphingomyelinase/ceramide pathway. The Journal of Cell Biology, 181, 335–350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Furchgott, R. F., & Vanhoutte, P. M. (1989). Endothelium-derived relaxing and contracting factors. The FASEB Journal, 3, 2007–2018.

    Article  CAS  PubMed  Google Scholar 

  102. Igarashi, J., Bernier, S. G., & Michel, T. (2001). Sphingosine 1-phosphate and activation of endothelial nitric-oxide synthase. Differential regulation of Akt and MAP kinase pathways by EDG and bradykinin receptors in vascular endothelial cells. The Journal of Biological Chemistry, 276, 12420–12426.

    Article  CAS  PubMed  Google Scholar 

  103. Morales-Ruiz, M., et al. (2001). Sphingosine 1-phosphate activates Akt, nitric oxide production, and chemotaxis through a Gi protein/phosphoinositide 3-kinase pathway in endothelial cells. The Journal of Biological Chemistry, 276, 19672–19677.

    Article  CAS  PubMed  Google Scholar 

  104. Dantas, A. P., Igarashi, J., & Michel, T. (2003). Sphingosine 1-phosphate and control of vascular tone. American Journal of Physiology. Heart and Circulatory Physiology, 284, H2045–H2052.

    Article  CAS  PubMed  Google Scholar 

  105. Cantalupo, A., et al. (2017). S1PR1 (Sphingosine-1-phosphate receptor 1) signaling regulates blood flow and pressure. Hypertension, 70, 426–434.

    Article  CAS  PubMed  Google Scholar 

  106. Nofer, J. R., et al. (2004). HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. The Journal of Clinical Investigation, 113, 569–581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Galvani, S., et al. (2015). HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Science Signaling, 8, ra79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Kappos, L., et al. (2010). A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. The New England Journal of Medicine, 362, 387–401.

    Article  CAS  PubMed  Google Scholar 

  109. Mandala, S., et al. (2002). Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science, 296, 346–349.

    Article  CAS  PubMed  Google Scholar 

  110. Paugh, S. W., Payne, S. G., Barbour, S. E., Milstien, S., & Spiegel, S. (2003). The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Letters, 554, 189–193.

    Article  CAS  PubMed  Google Scholar 

  111. Brinkmann, V., et al. (2002). The immune modulator FTY720 targets sphingosine 1-phosphate receptors. The Journal of Biological Chemistry, 277, 21453–21457.

    Article  CAS  PubMed  Google Scholar 

  112. Camm, J., Hla, T., Bakshi, R., & Brinkmann, V. (2014). Cardiac and vascular effects of fingolimod: Mechanistic basis and clinical implications. American Heart Journal, 168, 632–644.

    Article  CAS  PubMed  Google Scholar 

  113. Tolle, M., et al. (2005). Immunomodulator FTY720 induces eNOS-dependent arterial vasodilatation via the lysophospholipid receptor S1P3. Circulation Research, 96, 913–920.

    Article  PubMed  CAS  Google Scholar 

  114. Oo, M. L., et al. (2007). Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. The Journal of Biological Chemistry, 282, 9082–9089.

    Article  CAS  PubMed  Google Scholar 

  115. Mukhopadhyay, A., et al. (2009). Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling. The FASEB Journal, 23, 751–763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang, Q. J., et al. (2012). Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex. Diabetes, 61, 1848–1859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Bharath, L. P., et al. (2015). Ceramide-initiated protein phosphatase 2A activation contributes to arterial dysfunction in vivo. Diabetes, 64, 3914–3926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mehra, V. C., et al. (2014). Ceramide-activated phosphatase mediates fatty acid-induced endothelial VEGF resistance and impaired angiogenesis. The American Journal of Pathology, 184, 1562–1576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cantalupo, A., et al. (2020). Endothelial sphingolipid De novo synthesis controls blood pressure by regulating signal transduction and NO via ceramide. Hypertension, 75, 1279–1288.

    Article  CAS  PubMed  Google Scholar 

  120. Ogretmen, B., et al. (2002). Biochemical mechanisms of the generation of endogenous long chain ceramide in response to exogenous short chain ceramide in the A549 human lung adenocarcinoma cell line. Role for endogenous ceramide in mediating the action of exogenous ceramide. The Journal of Biological Chemistry, 277, 12960–12969.

    Article  CAS  PubMed  Google Scholar 

  121. Incalza, M. A., et al. (2018). Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascular Pharmacology, 100, 1–19.

    Article  CAS  PubMed  Google Scholar 

  122. Zhang, D. X., Zou, A. P., & Li, P. L. (2003). Ceramide-induced activation of NADPH oxidase and endothelial dysfunction in small coronary arteries. American Journal of Physiology. Heart and Circulatory Physiology, 284, H605–H612.

    Article  CAS  PubMed  Google Scholar 

  123. Zhang, A. Y., Yi, F., Zhang, G., Gulbins, E., & Li, P. L. (2006). Lipid raft clustering and redox signaling platform formation in coronary arterial endothelial cells. Hypertension, 47, 74–80.

    Article  CAS  PubMed  Google Scholar 

  124. Didion, S. P., & Faraci, F. M. (2005). Ceramide-induced impairment of endothelial function is prevented by CuZn superoxide dismutase overexpression. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 90–95.

    Article  CAS  PubMed  Google Scholar 

  125. Ikeda, Y., et al. (2015). Molecular mechanisms mediating mitochondrial dynamics and mitophagy and their functional roles in the cardiovascular system. Journal of Molecular and Cellular Cardiology, 78, 116–122.

    Article  CAS  PubMed  Google Scholar 

  126. Liu, Y., et al. (2003). Mitochondrial sources of H2O2 generation play a key role in flow-mediated dilation in human coronary resistance arteries. Circulation Research, 93, 573–580.

    Article  CAS  PubMed  Google Scholar 

  127. Sato, A., Sakuma, I., & Gutterman, D. D. (2003). Mechanism of dilation to reactive oxygen species in human coronary arterioles. American Journal of Physiology. Heart and Circulatory Physiology, 285, H2345–H2354.

    Article  CAS  PubMed  Google Scholar 

  128. Cai, H. (2005). Hydrogen peroxide regulation of endothelial function: Origins, mechanisms, and consequences. Cardiovascular Research, 68, 26–36.

    Article  CAS  PubMed  Google Scholar 

  129. Freed, J. K., Beyer, A. M., LoGiudice, J. A., Hockenberry, J. C., & Gutterman, D. D. (2014). Ceramide changes the mediator of flow-induced vasodilation from nitric oxide to hydrogen peroxide in the human microcirculation. Circulation Research, 115, 525–532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Schulz, M. E., Katunaric, B., Hockenberry, J. C., Gutterman, D. D., & Freed, J. K. (2019). Manipulation of the sphingolipid rheostat influences the mediator of flow-induced dilation in the human microvasculature. Journal of the American Heart Association, 8, e013153.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Oelze, M., et al. (2000). Vasodilator-stimulated phosphoprotein serine 239 phosphorylation as a sensitive monitor of defective nitric oxide/cGMP signaling and endothelial dysfunction. Circulation Research, 87, 999–1005.

    Article  CAS  PubMed  Google Scholar 

  132. Jung, B., et al. (2012). Flow-regulated endothelial S1P receptor-1 signaling sustains vascular development. Developmental Cell, 23, 600–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Versari, D., Daghini, E., Virdis, A., Ghiadoni, L., & Taddei, S. (2009). Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes Care, 32(Suppl 2), S314–S321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Forrest, M., et al. (2004). Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. The Journal of Pharmacology and Experimental Therapeutics, 309, 758–768.

    Article  CAS  PubMed  Google Scholar 

  135. Coussin, F., Scott, R. H., Wise, A., & Nixon, G. F. (2002). Comparison of sphingosine 1-phosphate-induced intracellular signaling pathways in vascular smooth muscles: Differential role in vasoconstriction. Circulation Research, 91, 151–157.

    Article  CAS  PubMed  Google Scholar 

  136. Salomone, S., et al. (2003). S1P3 receptors mediate the potent constriction of cerebral arteries by sphingosine-1-phosphate. European Journal of Pharmacology, 469, 125–134.

    Article  CAS  PubMed  Google Scholar 

  137. Lorenz, J. N., Arend, L. J., Robitz, R., Paul, R. J., & MacLennan, A. J. (2007). Vascular dysfunction in S1P2 sphingosine 1-phosphate receptor knockout mice. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 292, R440–R446.

    Article  CAS  PubMed  Google Scholar 

  138. Spijkers, L. J., Alewijnse, A. E., & Peters, S. L. (2012). FTY720 (fingolimod) increases vascular tone and blood pressure in spontaneously hypertensive rats via inhibition of sphingosine kinase. British Journal of Pharmacology, 166, 1411–1418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Fryer, R. M., et al. (2012). The clinically-tested S1P receptor agonists, FTY720 and BAF312, demonstrate subtype-specific bradycardia (S1P(1)) and hypertension (S1P(3)) in rat. PLoS One, 7, e52985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kappos, L., et al. (2006). Oral fingolimod (FTY720) for relapsing multiple sclerosis. The New England Journal of Medicine, 355, 1124–1140.

    Article  CAS  PubMed  Google Scholar 

  141. Di Raimondo, D., Musiari, G., & Pinto, A. (2020). Nocturnal blood pressure patterns and cardiac damage: There is still much to learn. Hypertension Research, 43, 246–248.

    Article  PubMed  Google Scholar 

  142. Yang, W. Y., et al. (2019). Association of office and ambulatory blood pressure with mortality and cardiovascular outcomes. JAMA, 322, 409–420.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Siedlinski, M., et al. (2017). Vascular transcriptome profiling identifies sphingosine kinase 1 as a modulator of angiotensin II-induced vascular dysfunction. Scientific Reports, 7, 44131.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Spijkers, L. J., et al. (2011). Hypertension is associated with marked alterations in sphingolipid biology: A potential role for ceramide. PLoS One, 6, e21817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Jones, S. P., & Bolli, R. (2006). The ubiquitous role of nitric oxide in cardioprotection. Journal of Molecular and Cellular Cardiology, 40, 16–23.

    Article  CAS  PubMed  Google Scholar 

  146. Keul, P., et al. (2016). Sphingosine-1-phosphate receptor 1 regulates cardiac function by modulating Ca2+ sensitivity and Na+/H+ exchange and mediates protection by ischemic preconditioning. Journal of the American Heart Association, 5, e003393.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Swendeman, S. L., et al. (2017). An engineered S1P chaperone attenuates hypertension and ischemic injury. Science Signaling, 10, eaal2722.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Mizugishi, K., et al. (2005). Essential role for sphingosine kinases in neural and vascular development. Molecular and Cellular Biology, 25, 11113–11121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Allende, M. L., et al. (2004). Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. The Journal of Biological Chemistry, 279, 52487–52492.

    Article  CAS  PubMed  Google Scholar 

  150. Kharel, Y., et al. (2012). Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate. The Biochemical Journal, 447, 149–157.

    Article  CAS  PubMed  Google Scholar 

  151. Olivera, A., et al. (2007). The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis. Immunity, 26, 287–297.

    Article  CAS  PubMed  Google Scholar 

  152. Furuya, H., et al. (2013). Effect of sphingosine kinase 1 inhibition on blood pressure. FASEB Journal, 27, 656–664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Gorshkova, I. A., et al. (2013). Inhibition of sphingosine-1-phosphate lyase rescues sphingosine kinase-1-knockout phenotype following murine cardiac arrest. Life Sciences, 93, 359–366.

    Article  CAS  PubMed  Google Scholar 

  154. Meissner, A., et al. (2017). Sphingosine-1-phosphate signalling-a key player in the pathogenesis of angiotensin II-induced hypertension. Cardiovascular Research, 113, 123–133.

    Article  CAS  PubMed  Google Scholar 

  155. Olivera, A., et al. (2010). Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock in mice. The Journal of Clinical Investigation, 120, 1429–1440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wilson, P. C., et al. (2015). Inhibition of sphingosine kinase 1 ameliorates angiotensin II-induced hypertension and inhibits transmembrane calcium entry via store-operated Calcium Channel. Molecular Endocrinology, 29, 896–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Takuwa, N., et al. (2010). S1P3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species. Cardiovascular Research, 85, 484–493.

    Article  CAS  PubMed  Google Scholar 

  158. Nagiec, M. M., Lester, R. L., & Dickson, R. C. (1996). Sphingolipid synthesis: Identification and characterization of mammalian cDNAs encoding the Lcb2 subunit of serine palmitoyltransferase. Gene, 177, 237–241.

    Article  CAS  PubMed  Google Scholar 

  159. Weiss, B., & Stoffel, W. (1997). Human and murine serine-palmitoyl-CoA transferase—cloning, expression and characterization of the key enzyme in sphingolipid synthesis. European Journal of Biochemistry, 249, 239–247.

    Article  CAS  PubMed  Google Scholar 

  160. Hornemann, T., Richard, S., Rutti, M. F., Wei, Y., & von Eckardstein, A. (2006). Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase. The Journal of Biological Chemistry, 281, 37275–37281.

    Article  CAS  PubMed  Google Scholar 

  161. Gable, K., et al. (2002). Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase. The Journal of Biological Chemistry, 277, 10194–10200.

    Article  CAS  PubMed  Google Scholar 

  162. McCampbell, A., et al. (2005). Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy. Human Molecular Genetics, 14, 3507–3521.

    Article  CAS  PubMed  Google Scholar 

  163. Beattie, A. E., et al. (2013). The pyridoxal 5′-phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT): Effects of the small subunits and insights from bacterial mimics of human hLCB2a HSAN1 mutations. BioMed Research International, 2013, 194371.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Hornemann, T., et al. (2009). The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. The Journal of Biological Chemistry, 284, 26322–26330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Choi, R. H., Tatum, S. M., Symons, J. D., Summers, S. A., & Holland, W. L. (2021). Ceramides and other sphingolipids as drivers of cardiovascular disease. Nature Reviews. Cardiology, 18(10), 701–711.

    Article  CAS  PubMed  Google Scholar 

  166. Sasset, L., Zhang, Y., Dunn, T. M., & Di Lorenzo, A. (2016). Sphingolipid de novo biosynthesis: A rheostat of cardiovascular homeostasis. Trends in Endocrinology and Metabolism, 27, 807–819.

    Article  CAS  PubMed  Google Scholar 

  167. Green, C. D., Maceyka, M., Cowart, L. A., & Spiegel, S. (2021). Sphingolipids in metabolic disease: The good, the bad, and the unknown. Cell Metabolism, 33, 1293–1306.

    Article  CAS  PubMed  Google Scholar 

  168. Ogretmen, B. (2018). Sphingolipid metabolism in cancer signalling and therapy. Nature Reviews. Cancer, 18, 33–50.

    Article  CAS  PubMed  Google Scholar 

  169. Han, G., et al. (2009). Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proceedings of the National Academy of Sciences of the United States of America, 106, 8186–8191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Harmon, J. M., et al. (2013). Topological and functional characterization of the ssSPTs, small activating subunits of serine palmitoyltransferase. The Journal of Biological Chemistry, 288, 10144–10153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Breslow, D. K., et al. (2010). Orm family proteins mediate sphingolipid homeostasis. Nature, 463, 1048–1053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Hjelmqvist, L., et al. (2002). ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins. Genome Biology, 3, RESEARCH0027.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Davis, D., Suemitsu, J., & Wattenberg, B. (2019). Transmembrane topology of mammalian ORMDL proteins in the endoplasmic reticulum as revealed by the substituted cysteine accessibility method (SCAM). Biochimica et Biophysica Acta—Proteins and Proteomics, 1867, 382–395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Li, S., Xie, T., Liu, P., Wang, L., & Gong, X. (2021). Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex. Nature Structural & Molecular Biology, 28, 249–257.

    Article  CAS  Google Scholar 

  175. Wang, Y., et al. (2021). Structural insights into the regulation of human serine palmitoyltransferase complexes. Nature Structural & Molecular Biology, 28, 240–248.

    Article  CAS  Google Scholar 

  176. Cantero-Recasens, G., Fandos, C., Rubio-Moscardo, F., Valverde, M. A., & Vicente, R. (2010). The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Human Molecular Genetics, 19, 111–121.

    Article  CAS  PubMed  Google Scholar 

  177. Siow, D. L., & Wattenberg, B. W. (2012). Mammalian ORMDL proteins mediate the feedback response in ceramide biosynthesis. The Journal of Biological Chemistry, 287, 40198–40204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Miller, M., et al. (2012). ORMDL3 is an inducible lung epithelial gene regulating metalloproteases, chemokines, OAS, and ATF6. Proceedings of the National Academy of Sciences of the United States of America, 109, 16648–16653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Gupta, S. D., et al. (2015). Expression of the ORMDLS, modulators of serine palmitoyltransferase, is regulated by sphingolipids in mammalian cells. The Journal of Biological Chemistry, 290, 90–98.

    Article  CAS  PubMed  Google Scholar 

  180. Sasset, L., et al. (2021). S1P controls endothelial sphingolipid homeostasis via ORMDL. bioRxiv, 2021.2010.2022.465503.

    Google Scholar 

  181. Moffatt, M. F., et al. (2007). Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature, 448, 470–473.

    Article  CAS  PubMed  Google Scholar 

  182. Schedel, M., et al. (2015). Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels. The Journal of Allergy and Clinical Immunology, 136, 893–903e814.

    Article  CAS  PubMed  Google Scholar 

  183. Miller, M., et al. (2014). ORMDL3 transgenic mice have increased airway remodeling and airway responsiveness characteristic of asthma. Journal of Immunology, 192, 3475–3487.

    Article  CAS  Google Scholar 

  184. Wang, H., Liu, Y., Shi, J., & Cheng, Z. (2019). ORMDL3 knockdown in the lungs alleviates airway inflammation and airway remodeling in asthmatic mice via JNK1/2-MMP-9 pathway. Biochemical and Biophysical Research Communications, 516, 739–746.

    Article  CAS  PubMed  Google Scholar 

  185. Clarke, B. A., et al. (2019). The Ormdl genes regulate the sphingolipid synthesis pathway to ensure proper myelination and neurologic function in mice. eLife, 8, e51067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Voeltz, G. K., Prinz, W. A., Shibata, Y., Rist, J. M., & Rapoport, T. A. (2006). A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell, 124, 573–586.

    Article  CAS  PubMed  Google Scholar 

  187. GrandPre, T., Nakamura, F., Vartanian, T., & Strittmatter, S. M. (2000). Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature, 403, 439–444.

    Article  CAS  PubMed  Google Scholar 

  188. Huber, A. B., Weinmann, O., Brosamle, C., Oertle, T., & Schwab, M. E. (2002). Patterns of Nogo mRNA and protein expression in the developing and adult rat and after CNS lesions. The Journal of Neuroscience, 22, 3553–3567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Yu, J., et al. (2009). Reticulon 4B (Nogo-B) is necessary for macrophage infiltration and tissue repair. Proceedings of the National Academy of Sciences of the United States of America, 106, 17511–17516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Acevedo, L., et al. (2004). A new role for Nogo as a regulator of vascular remodeling. Nature Medicine, 10, 382–388.

    Article  CAS  PubMed  Google Scholar 

  191. Bullard, T. A., et al. (2008). Identification of Nogo as a novel indicator of heart failure. Physiological Genomics, 32, 182–189.

    Article  CAS  PubMed  Google Scholar 

  192. Sarkey, J. P., et al. (2011). Nogo-A knockdown inhibits hypoxia/reoxygenation-induced activation of mitochondrial-dependent apoptosis in cardiomyocytes. Journal of Molecular and Cellular Cardiology, 50, 1044–1055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Zhang, Y., et al. (2016). Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload. JCI Insight, 1, e85484.

    Article  PubMed  PubMed Central  Google Scholar 

  194. Di Lorenzo, A., Manes, T. D., Davalos, A., Wright, P. L., & Sessa, W. C. (2011). Endothelial reticulon-4B (Nogo-B) regulates ICAM-1-mediated leukocyte transmigration and acute inflammation. Blood, 117, 2284–2295.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Xia, P., et al. (1998). Tumor necrosis factor-alpha induces adhesion molecule expression through the sphingosine kinase pathway. Proceedings of the National Academy of Sciences of the United States of America, 95, 14196–14201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Jones, S. P., et al. (1999). Myocardial ischemia-reperfusion injury is exacerbated in absence of endothelial cell nitric oxide synthase. The American Journal of Physiology, 276, H1567–H1573.

    CAS  PubMed  Google Scholar 

  197. Jones, S. P., et al. (2004). Endothelial nitric oxide synthase overexpression attenuates myocardial reperfusion injury. American Journal of Physiology. Heart and Circulatory Physiology, 286, H276–H282.

    Article  CAS  PubMed  Google Scholar 

  198. Cartier, A., & Hla, T. (2019). Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Science, 366, eaar5551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. de Carvalho, L. P., et al. (2018). Plasma ceramides as prognostic biomarkers and their arterial and myocardial tissue correlates in acute myocardial infarction. JACC Basic to Translational Science, 3, 163–175.

    Article  PubMed  PubMed Central  Google Scholar 

  200. Havulinna, A. S., et al. (2016). Circulating ceramides predict cardiovascular outcomes in the population-based FINRISK 2002 cohort. Arteriosclerosis, Thrombosis, and Vascular Biology, 36, 2424–2430.

    Article  CAS  PubMed  Google Scholar 

  201. Hilvo, M., et al. (2020). Development and validation of a ceramide- and phospholipid-based cardiovascular risk estimation score for coronary artery disease patients. European Heart Journal, 41, 371–380.

    Article  CAS  PubMed  Google Scholar 

  202. Laaksonen, R., et al. (2016). Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol. European Heart Journal, 37, 1967–1976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Peterson, L. R., et al. (2018). Ceramide remodeling and risk of cardiovascular events and mortality. Journal of the American Heart Association, 7, e007931.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Poss, A. M., et al. (2020). Machine learning reveals serum sphingolipids as cholesterol-independent biomarkers of coronary artery disease. The Journal of Clinical Investigation, 130, 1363–1376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Wang, D. D., et al. (2017). Plasma ceramides, Mediterranean diet, and incident cardiovascular disease in the PREDIMED trial (Prevencion con Dieta Mediterranea). Circulation, 135, 2028–2040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Gui, Y. K., et al. (2020). Plasma levels of ceramides relate to ischemic stroke risk and clinical severity. Brain Research Bulletin, 158, 122–127.

    Article  CAS  PubMed  Google Scholar 

  207. Fiedorowicz, A., Kozak-Sykala, A., Bobak, L., Kalas, W., & Strzadala, L. (2019). Ceramides and sphingosine-1-phosphate as potential markers in diagnosis of ischaemic stroke. Neurologia i Neurochirurgia Polska, 53, 484–491.

    Article  PubMed  Google Scholar 

  208. Mundra, P. A., et al. (2018). Large-scale plasma lipidomic profiling identifies lipids that predict cardiovascular events in secondary prevention. JCI Insight, 3, e121326.

    Article  PubMed Central  Google Scholar 

  209. Haus, J. M., et al. (2009). Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Diabetes, 58, 337–343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Hilvo, M., et al. (2018). Ceramide stearic to palmitic acid ratio predicts incident diabetes. Diabetologia, 61, 1424–1434.

    Article  CAS  PubMed  Google Scholar 

  211. Wigger, L., et al. (2017). Plasma dihydroceramides are diabetes susceptibility biomarker candidates in mice and humans. Cell Reports, 18, 2269–2279.

    Article  CAS  PubMed  Google Scholar 

  212. Ma, X., et al. (2015). ORMDL3 contributes to the risk of atherosclerosis in Chinese Han population and mediates oxidized low-density lipoprotein-induced autophagy in endothelial cells. Scientific Reports, 5, 17194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Kolter, T., & Sandhoff, K. (2006). Sphingolipid metabolism diseases. Biochimica et Biophysica Acta, 1758, 2057–2079.

    Article  CAS  PubMed  Google Scholar 

  214. Hicks, A. A., et al. (2009). Genetic determinants of circulating sphingolipid concentrations in European populations. PLoS Genetics, 5, e1000672.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Cresci, S., et al. (2020). Genetic architecture of circulating very-long-chain (C24:0 and C22:0) ceramide concentrations. Journal of Lipid and Atherosclerosis, 9, 172–183.

    Article  PubMed  PubMed Central  Google Scholar 

  216. Blackburn, N. B., et al. (2019). Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway. Journal of Lipid Research, 60, 1630–1639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Chaurasia, B., et al. (2019). Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science, 365, 386–392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Nicholson, R. J., et al. (2021). Characterizing a common CERS2 polymorphism in a mouse model of metabolic disease and in subjects from the Utah CAD study. The Journal of Clinical Endocrinology and Metabolism, 106, e3098–e3109.

    Article  PubMed  PubMed Central  Google Scholar 

  219. Good, D. A., et al. (2019). Noncoding variations in the gene encoding ceramide synthase 6 are associated with type 2 diabetes in a large indigenous Australian pedigree. Twin Research and Human Genetics, 22, 79–87.

    Article  PubMed  Google Scholar 

  220. Obinata, H., et al. (2014). Individual variation of human S1P(1) coding sequence leads to heterogeneity in receptor function and drug interactions. Journal of Lipid Research, 55, 2665–2675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Shendre, A., et al. (2017). Local ancestry and clinical cardiovascular events among African Americans from the atherosclerosis risk in communities study. Journal of the American Heart Association, 6, e004739.

    Article  PubMed  PubMed Central  Google Scholar 

  222. Domarkiene, I., et al. (2013). RTN4 and FBXL17 genes are associated with coronary heart disease in genome-wide association analysis of lithuanian families. Balkan Journal of Medical Genetics, 16, 17–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health grants R01 HL126913 and R01 HL152195 to A. Di Lorenzo.

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  1. Department of Pathology and Laboratory Medicine, Cardiovascular Research Institute, Feil Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA

    Linda Sasset & Annarita Di Lorenzo

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Correspondence to Annarita Di Lorenzo .

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  1. Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA

    Xian-Cheng Jiang

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Sasset, L., Di Lorenzo, A. (2022). Sphingolipid Metabolism and Signaling in Endothelial Cell Functions. In: Jiang, XC. (eds) Sphingolipid Metabolism and Metabolic Disease. Advances in Experimental Medicine and Biology, vol 1372. Springer, Singapore. https://doi.org/10.1007/978-981-19-0394-6_8

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