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Sphingolipids in essential hypertension and endothelial dysfunction
Spijkers, L.J.A.
Publication date
2013
Link to publication
Citation for published version (APA):
Spijkers, L. J. A. (2013). Sphingolipids in essential hypertension and endothelial dysfunction.
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209
As mentioned in Chapter 1, the biological systems in which sphingolipids are involved are numerous and progressively expanding. The emerging implications of sphingolipid signalling in several disease states are briefly discussed in this addendum, ranging from a monogenetic disease state towards more complex polygenetic/multifactorial systems. These include; sphingolipidoses, immune function and inflammation, cancer and diabetes mellitus. Most of the systems described in the following subparagraphs have associations with the previously described chapters, and hence are included in this thesis book for brief additional information.
Sphingolipidoses
The inability to break down specific sphingolipids, leading to malignant accumulating levels in subcellular compartments, forms a subclass of lipid storage disorders denoted as sphingolipidoses. Sphingolipidoses can be differentiated into several subclasses based on the specific sphingolipid-catabolising enzyme deficiency. These include for instance; morbus Niemann-Pick (SM accumulation), Tay-Sachs (GM2), Fabry (GB3), Krabbe (GalCer and other sphingolipids) and Gaucher (GlcCer). The specific pathological consequences of these malignancies depend on the specific sphingolipid and target organ of accumulation. In Gaucher disease, characterized by the inability to clear glucosylceramide due to insufficient lysosomal glucocerebrosidase activity, the accumulation of glucosylceramide and glucosylsphingosine in tissue (spleen, liver, bone marrow) and in circulation 1,2 causes an inflammatory and
insulin-resistant phenotype 3, and several sphingolipid accumulation-associated complications (e.g.
hepatosplenomegaly, pancytopenia and bone complications) have been commonly described.
Immune function and inflammation
The complexity of the immune system can be exemplified by the abundant and differential crosstalk with sphingolipids. The identification of the novel S1P receptor agonist fingolimod (FTY720), which has successfully been introduced to treat relapsing multiple sclerosis, centred much attention on the immune modulatory potential of sphingolipids.FTY720 is a sphingosine analogue that is phosphorylated in vivo to (S)-FTY720-P by sphingosine kinase 4,5. FTY720-P is a
Supporting
information
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high affinity ligand at four of the five S1P-receptors (S1P1,3,4,5) and binding to T-lymphocytes
leads to degradation of the membrane-presented S1P1 receptors, which subsequently results in
a reduced lymphocyte egress and thus a T-lymphocyte-specific immunosuppression 6. Indeed,
the importance of S1P1-signalling on the preservation of immune function is further exemplified
in a study on hibernating animals, in which low body temperature decreases circulating S1P levels with a concomitant regression in circulating lymphocytes. Indeed, restoration of lymphocyte egress in this model could be blocked by the S1P1-specific antagonist W146 7. Yet,
immune suppressive treatment of renal transplant patients by FTY720-P 8 resulted in marked
adverse events, indicating a still immature insight in both efficacy and safety of S1P receptor-based immunomodulation 9. Next to S1P, the involvement of C1P in immune function
protection has been indicated in a CerK-deficient animal model, which displayed pronounced neutropenia and impaired capacity to target bacterial infections 10. Recently, both S1P and C1P
have been shown to be involved in inflammatory processes. Cyclooxygenase (COX)-2 products contribute to inflammatory processes and its expression can be upregulated upon SK activation 11. Furthermore, activation of COX-2 appears dependent on CERT-mediated transport
of ceramide and subsequent C1P production by CerK. C1P appears to be required for cPLA2α translocation towards the Golgi system, which generates arachidonic acid as a substrate molecule for COX-2 12. Next to this, a key feature of inflammation in the vasculature is
endothelial cell barrier function disruption, leading to vascular leakage which supports endothelial transmigration of white blood cells. Both the endothelial S1P1 and S1P3 receptors
are implicated in this regulation, although with opposite outcome on barrier integrity13-15. Next
to barrier disruption, endothelial cell activation (as present in hypertension), involves elevated expression of cell adhesion molecules located at the endothelial cell membrane. In these cells, S1P-induced stimulation of adhesion molecule expression has been shown for e.g. vascular cell adhesion molecule (VCAM), monocyte chemotactic protein (MCP)-1 and E-selectin 16,17.
Cancer onset and progression
Over a decade ago, Weinberg and Hannahan described the essential physiological alterations within cells to eventually give rise to cancer onset and progression, to uniformly postulate the six hallmarks of cancer 18. These hallmarks comprise; self-sufficiency in growth signalling,
insensitivity to growth-inhibitory signals, evasion of apoptosis, unlimited replication potential, sustained angiogenesis, and tissue invasion and metastasis. In this respect, sphingolipids have been shown to play a role in most, if not all, of these hallmarks.
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Angiogenesis is a key process for sustaining tumour growth by expanding tumour vascularisation, thus delivery of nutrients and oxygen. Lee et al. indicated an interplay of S1P with vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signalling to promote angiogenesis 19. Indeed, in a murine mammary carcinoma model, angiogenesis was
depended on S1P signalling 20. Next to S1P, also C1P has been implicated in regulating
angiogenesis, and this process was found to be impaired in CerK-deficient micro-endothelial cells stimulated to initiate angiogenic processes 21. In HUVECs, S1P signalling induced S1P
1
-mediated cell migration, an important malignant feature of tumour tissue invasion and metastasis 22. In MCF-7 cells, S1P induced cellular migration, however S1P
3 rather than S1P1
was involved, clearly coupling both receptors to this mechanism 23.
In contrast to the apoptotic effector ceramide, S1P is generally accepted as being proliferative, and evidence for anti-apoptotic properties of S1P have been established unambiguously 24,25.
Indeed, many cancer cell lines display elevated SK1 expression to sustain growth and survival 26.
In HUVECs, SK1 activation is associated with PI3K/Akt activation, a key protein synthesis and survival pathway, and upregulation of the survival protein Bcl-2 27. Consequently, inhibition of
SK1 expression in MCF-7 cancer cells leads to apoptosis and growth arrest, confirming the proto-oncogenic nature of S1P 28. Pyne et al. recently demonstrated that high SK1 expression in
a specific breast cancer subset correlated with poor survival and a chemotherapy-resistant phenotype 23.
Finally, a large variety of mechanisms involved in chemotherapy resistance have been explored, and sphingolipids are postulated to participate in these mechanisms. Important regulators involved in drug resistance are the drug efflux proteins: multidrug-resistance-related protein 1 (MRP1) and p-glycoprotein (Pgp). High expression of these efflux proteins in several cancer cell types is associated with an altered sphingolipid presence. For instance, elevated gangliosides (i.e. GD2, GM3, GD3) are postulated to modulate efflux protein function, either directly or indirectly via lipid raft composition modification, thus modulating drug resistance in these cells 29-31.
Diabetes mellitus
In both type 1 as well as type 2 diabetes mellitus, evidence for sphingolipid involvement have been reported. In type 1 diabetes, characterised by autoantibody-directed destruction of pancreatic β-cells 32, sphingolipid biology is altered. The implication of sphingolipids in this
Supporting information
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glycosphingolipids (which are highly present in pancreatic islet cells) in diabetic patients’ sera 33-35. In a genetic mouse model of diabetes, S1P levels were elevated both in blood plasma as well
as heart tissue compared to control animals 36, possibly due to hyperglycaemia-induced SK1
activation 37,38. Indeed, recently, a role for S1P has been established in mediating
glucose-induced insulin secretion from pancreatic beta cells 39. In a diabetic model, the C24:1 subset of
sphingomyelin, ceramide and cerebrosides were found to be decreased in plasma compared to controls. In retina and renal tissue of pharmacologically-induced diabetes models, ceramide was also found to be decreased, however with a concomitant increase in GlcCer levels 40,41.
Interestingly, treatment of insulin-resistant animals with the compound AMP-DNM, a glucosylceramide synthase inhibitor, restored insulin sensitivity 42. Mechanistic insight into the
pathological condition of type 2 diabetes, has provided membrane microdomain dysfunction as an interesting possible cause. In this case, the binding of insulin to the insulin receptor (IR) causes, by migration from the plasma membrane microdomains towards caveolae, translocation of the glucose transporter 4 (GLUT4) towards the plasma membrane for eventually glucose uptake 43,44. The glycosphingolipid GM3 is in close association with the IR in the plasma
microdomains, and high abundance of GM3 likely prevents the migration of the IR towards caveolae, thus inhibiting glucose uptake 45. In agreement with this, diabetic humans and animal
models displayed elevated tissue ceramide levels, which is the precursor sphingolipid for e.g. GlcCer and subsequently GM3, and which is found to be concentration-dependently associated with the severity of insulin resistance 46-48. These latter findings provide a basis for ceramide and
its metabolites in diabetes. Recent studies indicate that ceramide lowering is indeed associated with restored insulin sensitivity 49-50.
The findings summarised in this supporting information emphasize the involvement of sphingolipid biology in several pathophysiological signalling systems. A growing number of tools to monitor and alter sphingolipid presence warrant an emerging focus on the role of sphingolipids in these disease states, and a better understanding of whether these oppose attractive markers or treatment targets.
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References
1. Ghauharali-van der Vlugt K, Langeveld M, Poppema A, Kuiper S, Hollak CE, Aerts JM, Groener JE. Prominent increase in plasma ganglioside GM3 is associated with clinical manifestations of type I Gaucher disease. Clin Chim Acta 2008; 389(1-2):109-113. 2. Dekker N, van DL, Hollak CE, Overkleeft H, Scheij S, Ghauharali K, van Breemen MJ,
Ferraz MJ, Groener JE, Maas M, Wijburg FA, Speijer D, Tylki-Szymanska A, Mistry PK, Boot RG, Aerts JM. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response. Blood 2011; 118(16):e118-e127.
3. Mizukami H, Mi Y, Wada R, Kono M, Yamashita T, Liu Y, Werth N, Sandhoff R, Sandhoff K, Proia RL. Systemic inflammation in glucocerebrosidase-deficient mice with minimal glucosylceramide storage. J Clin Invest 2002; 109(9):1215-1221.
4. Billich A, Bornancin F, Devay P, Mechtcheriakova D, Urtz N, Baumruker T. Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J Biol Chem 2003; 278(48):47408-47415.
5. Albert R, Hinterding K, Brinkmann V, Guerini D, Muller-Hartwieg C, Knecht H, Simeon C, Streiff M, Wagner T, Welzenbach K, Zecri F, Zollinger M, Cooke N, Francotte E. Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomer. J Med Chem 2005; 48(16):5373-5377.
6. Chiba K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Ther 2005; 108(3):308-319.
7. Bouma HR, Kroese FG, Kok JW, Talaei F, Boerema AS, Herwig A, Draghiciu O, van BA, Epema AH, van DA, Strijkstra AM, Henning RH. Low body temperature governs the decline of circulating lymphocytes during hibernation through sphingosine-1-phosphate. Proc Natl Acad Sci U S A 2011; 108(5):2052-2057.
8. Tedesco-Silva H, Szakaly P, Shoker A, Sommerer C, Yoshimura N, Schena FP, Cremer M, Hmissi A, Mayer H, Lang P. FTY720 versus mycophenolate mofetil in de novo renal transplantation: six-month results of a double-blind study. Transplantation 2007; 84(7):885-892.
9. Rosen H, Gonzalez-Cabrera P, Marsolais D, Cahalan S, Don AS, Sanna MG. Modulating tone: the overture of S1P receptor immunotherapeutics. Immunol Rev 2008; 223:221-235.
Supporting information
214
10. Graf C, Zemann B, Rovina P, Urtz N, Schanzer A, Reuschel R, Mechtcheriakova D, Muller M, Fischer E, Reichel C, Huber S, Dawson J, Meingassner JG, Billich A, Niwa S, Badegruber R, Van Veldhoven PP, Kinzel B, Baumruker T, Bornancin F. Neutropenia with impaired immune response to Streptococcus pneumoniae in ceramide kinase-deficient mice. J Immunol 2008; 180(5):3457-3466.
11. Pettus BJ, Bielawski J, Porcelli AM, Reames DL, Johnson KR, Morrow J, Chalfant CE, Obeid LM, Hannun YA. The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-alpha. FASEB J 2003; 17(11):1411-1421.
12. Lamour NF, Stahelin RV, Wijesinghe DS, Maceyka M, Wang E, Allegood JC, Merrill AH, Jr., Cho W, Chalfant CE. Ceramide kinase uses ceramide provided by ceramide transport protein: localization to organelles of eicosanoid synthesis. J Lipid Res 2007; 48(6):1293-1304.
13. Bombeli T, Mueller M, Haeberli A. Anticoagulant properties of the vascular endothelium. Thromb Haemost 1997; 77(3):408-423.
14. Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 2005; 105(8):3178-3184.
15. Singleton PA, Moreno-Vinasco L, Sammani S, Wanderling SL, Moss J, Garcia JG. Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation. Am J Respir Cell Mol Biol 2007; 37(2):222-231.
16. Chen XL, Grey JY, Thomas S, Qiu FH, Medford RM, Wasserman MA, Kunsch C. Sphingosine kinase-1 mediates TNF-alpha-induced MCP-1 gene expression in endothelial cells: upregulation by oscillatory flow. Am J Physiol Heart Circ Physiol 2004; 287(4):H1452-H1458.
17. Xia P, Gamble JR, Rye KA, Wang L, Hii CS, Cockerill P, Khew-Goodall Y, Bert AG, Barter PJ, Vadas MA. Tumor necrosis factor-alpha induces adhesion molecule expression through the sphingosine kinase pathway. Proc Natl Acad Sci U S A 1998; 95(24):14196-14201.
18. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100(1):57-70.
19. Lee OH, Kim YM, Lee YM, Moon EJ, Lee DJ, Kim JH, Kim KW, Kwon YG. Sphingosine 1-phosphate induces angiogenesis: its angiogenic action and signaling mechanism in human umbilical vein endothelial cells. Biochem Biophys Res Commun 1999; 264(3):743-750.
20. Nagahashi M, Ramachandran S, Kim EY, Allegood JC, Rashid OM, Yamada A, Zhao R, Milstien S, Zhou H, Spiegel S, Takabe K. Sphingosine-1-phosphate produced by
215
sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesi. Cancer Res 2012; 72(3):726-735.
21. Niwa S, Graf C, Bornancin F. Ceramide kinase deficiency impairs microendothelial cell angiogenesis in vitro. Microvasc Res 2009; 77(3):389-393.
22. Wang F, Van Brocklyn JR, Hobson JP, Movafagh S, Zukowska-Grojec Z, Milstien S, Spiegel S. Sphingosine 1-phosphate stimulates cell migration through a G(i)-coupled cell surface receptor. Potential involvement in angiogenesis. J Biol Chem 1999; 274(50):35343-35350.
23. Pyne NJ, Tonelli F, Lim KG, Long JS, Edwards J, Pyne S. Sphingosine 1-phosphate signalling in cancer. Biochem Soc Trans 2012; 40(1):94-100.
24. Chalfant CE, Spiegel S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci 2005; 118(Pt 20):4605-4612.
25. Nava VE, Hobson JP, Murthy S, Milstien S, Spiegel S. Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells. Exp Cell Res 2002; 281(1):115-127.
26. Lim KG, Gray AI, Pyne S, Pyne NJ. Resveratrol Dimers Are Novel Sphingosine Kinase 1 Inhibitors and Affect Sphingosine Kinase 1 Expression and Cancer Cell Growth and Survival. Br J Pharmacol 2012.
27. Limaye V, Li X, Hahn C, Xia P, Berndt MC, Vadas MA, Gamble JR. Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-kinase-1-dependent activation of PI-3K/Akt and regulation of Bcl-2 family members. Blood 2005; 105(8):3169-3177. 28. Taha TA, Kitatani K, El-Alwani M, Bielawski J, Hannun YA, Obeid LM. Loss of
sphingosine kinase-1 activates the intrinsic pathway of programmed cell death: modulation of sphingolipid levels and the induction of apoptosis. FASEB J 2006; 20(3):482-484.
29. Klappe K, Hinrichs JW, Kroesen BJ, Sietsma H, Kok JW. MRP1 and glucosylceramide are coordinately over expressed and enriched in rafts during multidrug resistance acquisition in colon cancer cells. Int J Cancer 2004; 110(4):511-522.
30. Dijkhuis AJ, Douwes J, Kamps W, Sietsma H, Kok JW. Differential expression of sphingolipids in P-glycoprotein or multidrug resistance-related protein 1 expressing human neuroblastoma cell lines. FEBS Lett 2003; 548(1-3):28-32.
31. Hummel I, Klappe K, Kok JW. Up-regulation of lactosylceramide synthase in MDR1 overexpressing human liver tumour cells. FEBS Lett 2005; 579(16):3381-3384.
32. Castano L, Eisenbarth GS. Type-I diabetes: a chronic autoimmune disease of human, mouse, and rat. Annu Rev Immunol 1990; 8:647-679.
Supporting information
216
33. Tiberti C, Dotta F, Anastasi E, Torresi P, Multari G, Vecci E, Andreani D, Di MU. Anti-ganglioside antibodies in new onset type 1 diabetic patients and high risk subjects. Autoimmunity 1995; 22(1):43-48.
34. Gillard BK, Thomas JW, Nell LJ, Marcus DM. Antibodies against ganglioside GT3 in the sera of patients with type I diabetes mellitus. J Immunol 1989; 142(11):3826-3832. 35. Nayak RC, Omar MA, Rabizadeh A, Srikanta S, Eisenbarth GS. "Cytoplasmic" islet cell
antibodies. Evidence that the target antigen is a sialoglycoconjugate. Diabetes 1985; 34(6):617-619.
36. Fox TE, Bewley MC, Unrath KA, Pedersen MM, Anderson RE, Jung DY, Jefferson LS, Kim JK, Bronson SK, Flanagan JM, Kester M. Circulating sphingolipid biomarkers in models of type 1 diabetes. J Lipid Res 2011; 52(3):509-517.
37. Wang L, Xing XP, Holmes A, Wadham C, Gamble JR, Vadas MA, Xia P. Activation of the sphingosine kinase-signaling pathway by high glucose mediates the proinflammatory phenotype of endothelial cells. Circ Res 2005; 97(9):891-899.
38. You B, Ren A, Yan G, Sun J. Activation of sphingosine kinase-1 mediates inhibition of vascular smooth muscle cell apoptosis by hyperglycemia. Diabetes 2007; 56(5):1445-1453.
39. Stanford JC, Morris AJ, Sunkara M, Popa GJ, Larson KL, Ozcan S. Sphingosine-1 phosphate (S1P) regulates glucose-stimulated insulin secretion in pancreatic beta cells. J Biol Chem 2012.
40. Fox TE, Han X, Kelly S, Merrill AH, Martin RE, Anderson RE, Gardner TW, Kester M. Diabetes alters sphingolipid metabolism in the retina: a potential mechanism of cell death in diabetic retinopathy. Diabetes 2006; 55(12):3573-3580.
41. Zador IZ, Deshmukh GD, Kunkel R, Johnson K, Radin NS, Shayman JA. A role for glycosphingolipid accumulation in the renal hypertrophy of streptozotocin-induced diabetes mellitus. J Clin Invest 1993; 91(3):797-803.
42. Aerts JM, Ottenhoff R, Powlson AS, Grefhorst A, van EM, Dubbelhuis PF, Aten J, Kuipers F, Serlie MJ, Wennekes T, Sethi JK, O'Rahilly S, Overkleeft HS. Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 2007; 56(5):1341-1349.
43. Inokuchi J. Physiopathological function of hematoside (GM3 ganglioside). Proc Jpn Acad Ser B Phys Biol Sci 2011; 87(4):179-198.
44. Bikman BT, Summers SA. Ceramides as modulators of cellular and whole-body metabolism. J Clin Invest 2011; 121(11):4222-4230.
217
45. Tagami S, Inokuchi JJ, Kabayama K, Yoshimura H, Kitamura F, Uemura S, Ogawa C, Ishii A, Saito M, Ohtsuka Y, Sakaue S, Igarashi Y. Ganglioside GM3 participates in the pathological conditions of insulin resistance. J Biol Chem 2002; 277(5):3085-3092. 46. Adams JM, Pratipanawatr T, Berria R, Wang E, Defronzo RA, Sullards MC, Mandarino
LJ. Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes 2004; 53(1):25-31.
47. Haus JM, Kashyap SR, Kasumov T, Zhang R, Kelly KR, Defronzo RA, Kirwan JP. Plasma ceramides are elevated in obese subjects with type 2 diabetes and correlate with the severity of insulin resistance. Diabetes 2009; 58(2):337-343.
48. Straczkowski M, Kowalska I, Baranowski M, Nikolajuk A, Otziomek E, Zabielski P, Adamska A, Blachnio A, Gorski J, Gorska M. Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes. Diabetologia 2007; 50(11):2366-2373. 49. Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, Narra K, Hoehn
KL, Knotts TA, Siesky A, Nelson DH, Karathanasis SK, Fontenot GK, Birnbaum MJ, Summers SA. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 2007; 5(3):167-179.
50. Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM, Bulchand S, Knotts TA, Shui G, Clegg DJ, Wenk MR, Pagliassotti MJ, Scherer PE, Summers SA. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 2011; 121(5):1858-1870.
