Abstract
The pathogenic basis of abnormal placentation and dysfunction in preeclampsia (PE) is highly complex and incompletely understood. Secretory sphyngomyelinase activity (S-ASM) was analyzed in plasma samples from 158 pregnant women developing PE and 112 healthy pregnant controls. Serum PlGF, sFlt-1, s-Endoglin and sVCAM were measured. Results showed S-ASM activity to be higher in women who later developed PE than in those with uncomplicated pregnancies (40.6% and 28.8% higher in the late- and early-onset groups, respectively). Plasma S-ASM activity correlated significantly with circulating markers of endothelial damage in the late-PE group (endoglin and sVCAM-1), with plasma cholesterol and total lipid levels. However, these significant associations were not observed in the early-PE or control groups. This work provides the first evidence of significantly elevated circulating S-ASM activity in the first trimester of pregnancy in women who go on to develop PE; thus, it may be deduced that the circulating form of ASM is biologically active in PE and could contribute to promoting endothelial dysfunction and cardiovascular programming. Plasma S-ASM measurement may have clinical relevance as a further potential biomarker contributing to the earliest identification of women at risk of developing preeclampsia.
Acknowledgments
Dr. Rodríguez-Sureda is supported by the Centre for Biomedical Network Research on Rare Diseases (CIBERER) from Instituto de Salud Carlos III. The study was supported in part by grants from Fondo de Investigaciones Sanitarias (FIS PI12/00851 and FIS PI13/01449). The samples used in this Project were provided by the Hospital Clínic-IDIBAPS Biobank and Biobanc HUVH with an appropiate ethical approval. We are grateful to Miss C. O’Hara for her help in editing the English language in the original manuscript.
References
Allen, R. E., Rogozinska, E., Cleverly, K., Aquilina, J., and Thangaratinam, S. (2014). Abnormal blood biomarkers in early pregnancy are associated with preeclampsia: a meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 182, 194–201.10.1016/j.ejogrb.2014.09.027Search in Google Scholar PubMed
Brown, M.A., Lindheimer, M.D., de Swiet, M., Van Assche, A., and Moutquin, J.M. (2001). The classification and diagnosis of the hypertensive disorders of pregnancy: Statement from the international society for the study of hypertension in pregnancy (iSSHP). Hypertens. Pregnancy 20, IX–XIV.Search in Google Scholar
Chalas, J., Audibert, F., Francoual, J., Le Bihan, B., Frydman, R., and Lindenbaum, A. (2002). Concentrations of apolipoproteins E, C2, and C3 and lipid profile in preeclampsia. Hypertens. Pregnancy 21, 199–204.10.1081/PRG-120015846Search in Google Scholar PubMed
Claus, R.A., Bunck, A.C., Bockmeyer, C.L., Brunkhorst, F.M., Lösche, W., Kinscherf, R., and Deigner, H.-P. (2005). Role of increased sphingomyelinase activity in apoptosis and organ failure of patients with severe sepsis. FASEB J. 19, 1719–1721.10.1096/fj.04-2842fjeSearch in Google Scholar PubMed
Clausen, T., Djurovic, S., and Henriksen, T. (2001). Dyslipidemia in early second trimester is mainly a feature of women with early onset pre-eclampsia. Br. J. Obstet. Gynaecol. 108, 1081–1087.Search in Google Scholar
Crispi, F., Domínguez, C., Llurba, E., Martín-Gallán, P., Cabero, L., and Gratacós, E. (2006). Placental angiogenic growth factors and uterine artery doppler findings for characterization of different subsets in preeclampsia and in isolated intrauterine growth restriction. Am. J. Obstet. Gynecol. 195, 201–207.10.1016/j.ajog.2006.01.014Search in Google Scholar PubMed
Crispi, F., Llurba, E., Domínguez, C., Martín-Gallán, P., Cabero, L., and Gratacós, E. (2008). Predictive value of angiogenic factors and uterine artery doppler for early- versus late-onset pre-eclampsia and intrauterine growth restriction. Ultrasound Obstet. Gynecol. 31, 303–309.10.1002/uog.5184Search in Google Scholar PubMed
Crovetto, F., Figueras, F., Triunfo, S., Crispi, F., Rodríguez-Sureda, V., Peguero, A., Domínguez, C., and Gratacós, E. (2014). Added value of angiogenic factors for the prediction of early and late preeclampsia in the first trimester of pregnancy. Fetal Diagn. Ther. 35, 258–266.10.1159/000358302Search in Google Scholar PubMed
Crovetto, F., Figueras, F., Triunfo, S., Crispi, F., Rodriguez-Sureda, V., Dominguez, C., Llurba, E., and Gratacós, E. (2015). First trimester screening for early and late preeclampsia based on maternal characteristics, biophysical parameters, and angiogenic factors. Prenat. Diagn. 35, 183–191.10.1002/pd.4519Search in Google Scholar PubMed
Diggelen, O.P. van, Voznyi, Y.V., Keulemans, J.L.M., Schoonderwoerd, K., Ledvinova, J., Mengel, E., Zschiesche, M., Santer, R., and Harzer, K. (2005). A new fluorimetric enzyme assay for the diagnosis of Niemann-Pick A/B, with specificity of natural sphingomyelinase substrate. J. Inherit. Metab. Dis. 28, 733–741.10.1007/s10545-005-0105-ySearch in Google Scholar PubMed
Doehner, W., Bunck, A.C., Rauchhaus, M., von Haehling, S., Brunkhorst, F.M., Cicoira, M., Tschope, C., Ponikowski, P., Claus, R.A., and Anker, S.D. (2007). Secretory sphingomyelinase is upregulated in chronic heart failure: a second messenger system of immune activation relates to body composition, muscular functional capacity, and peripheral blood flow. Eur. Heart J. 28, 821–828.10.1093/eurheartj/ehl541Search in Google Scholar PubMed
Eiland, E., Nzerue, C., and Faulkner, M. (2012). Preeclampsia 2012. J. Pregnancy 2012, 586578.10.1155/2012/586578Search in Google Scholar PubMed PubMed Central
Emet, T., Işik, Ü., Güven, S.G., Balik, G., Ural, Ü.M., Tekin, Y.B., Šentürk, Š., Šahin, F.K., and Avşar, A.F. (2013). Plasma lipids and lipoproteins during pregnancy and related pregnancy outcomes. Arch. Gynecol. Obstet. 288, 49–55.10.1007/s00404-013-2750-ySearch in Google Scholar PubMed
Enquobahrie, D.A., Williams, M.A., Butler, C.L., Frederick, I.O., Miller, R.S., and Luthy, D.A. (2004). Maternal plasma lipid concentrations in early pregnancy and risk of preeclampsia. Am. J. Hypertens. 17, 574–581.10.1016/j.amjhyper.2004.03.666Search in Google Scholar PubMed
Farzadnia, M., Ayatollahi, H., Hasan-Zade, M., and Rahimi, H.R. (2013). A comparative study of vascular cell adhesion molecule-1 and high-sensitive C-reactive protein in normal and preeclamptic pregnancies. Interv. Med. Appl. Sci. 5, 26–30.10.1556/imas.5.2013.1.5Search in Google Scholar
García-Ruiz, C., Marí, M., Morales, A., Colell, A., Ardite, E., and Fernández-Checa, J.C. (2000). Human placenta sphingomyelinase, an exogenous acidic pH-optimum sphingomyelinase, induces oxidative stress, glutathione depletion, and apoptosis in rat hepatocytes. Hepatology 32, 56–65.10.1053/jhep.2000.8267Search in Google Scholar PubMed
Germain, S.J., Sacks, G.P., Sooranna, S.R., Soorana, S.R., Sargent, I.L., and Redman, C.W. (2007). Systemic inflammatory priming in normal pregnancy and preeclampsia: the role of circulating syncytiotrophoblast microparticles. J. Immunol. 178, 5949–5956.10.4049/jimmunol.178.9.5949Search in Google Scholar PubMed
Ghulmiyyah, L. and Sibai, B. (2012). Maternal mortality from preeclampsia/eclampsia. Semin. Perinatol. 36, 56–59.10.1053/j.semperi.2011.09.011Search in Google Scholar PubMed
Grammatikos, G., Mühle, C., Ferreiros, N., Schroeter, S., Bogdanou, D., Schwalm, S., Hintereder, G., Kornhuber, J., Zeuzem, S., Sarrazin, C., et al. (2014). Serum acid sphingomyelinase is upregulated in chronic hepatitis C infection and non alcoholic fatty liver disease. Biochim. Biophys. Acta 1841, 1012–1020.10.1016/j.bbalip.2014.04.007Search in Google Scholar PubMed
Gulbins, E. and Kolesnick, R. (2002). Acid sphingomyelinase-derived ceramide signaling in apoptosis. Subcell. Biochem. 36, 229–244.10.1007/0-306-47931-1_12Search in Google Scholar PubMed
Hannun, Y.A. and Obeid, L.M. (2008). Principles of bioactive lipid signalling: Lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 9, 139–150.10.1038/nrm2329Search in Google Scholar PubMed
Hou, Q., Jin, J., Zhou, H., Novgorodov, S.A., Bielawska, A., Szulc, Z.M., Hannun, Y.A., Obeid, L.M., and Hsu, Y.-T. (2011). Mitochondrially targeted ceramides preferentially promote autophagy, retard cell growth, and induce apoptosis. J. Lipid Res. 52, 278–288.10.1194/jlr.M012161Search in Google Scholar PubMed PubMed Central
Hund, M., Verhagen-Kamerbeek, W., Reim, M., Messinger, D., van der Does, R., and Stepan, H. (2015). Influence of the sFlt-1/PlGF ratio on clinical decision-making in women with suspected preeclampsia – the preOS study protocol. Hypertens. Pregnancy 34, 102–115.10.3109/10641955.2014.982331Search in Google Scholar
Hurwitz, R., Ferlinz, K., Vielhaber, G., Moczall, H., and Sandhoff, K. (1994). Processing of human acid sphingomyelinase in normal and I-cell fibroblasts. J. Biol. Chem. 269, 5440–5445.10.1016/S0021-9258(17)37705-0Search in Google Scholar
Jenkins, R.W., Canals, D., and Hannun, Y.A. (2009). Roles and regulation of secretory and lysosomal acid sphingomyelinase. Cell Signal. 21, 836–846.10.1016/j.cellsig.2009.01.026Search in Google Scholar
Jenkins, R.W., Clarke, C.J., Lucas, J.T., Jr, Shabbir, M., Wu, B.X., Simbari, F., Mueller, J., Hannun, Y.A., Lazarchick, J., and Shirai, K. (2013). Evaluation of the role of secretory sphingomyelinase and bioactive sphingolipids as biomarkers in hemophagocytic lymphohistiocytosis. Am. J. Hematol. 88, E265–E272.10.1002/ajh.23535Search in Google Scholar
Kendall, R.L. and Thomas, K.A. (1993). Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc. Natl. Acad. Sci. USA 90, 10705–10709.10.1073/pnas.90.22.10705Search in Google Scholar
Kleinrouweler, C.E., Wiegerinck, M.M.J., Ris-Stalpers, C., Bossuyt, P.M.M., van der Post, J.A.M., von Dadelszen, P., Mol, B.W.J., and Pajkrt, E. (2012). Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis. BJOG 119, 778–787.10.1111/j.1471-0528.2012.03311.xSearch in Google Scholar
Koçyigit, Y., Atamer, Y., Atamer, A., Tuzcu, A., and Akkus, Z. (2004). Changes in serum levels of leptin, cytokines and lipoprotein in pre-eclamptic and normotensive pregnant women. Gynecol. Endocrinol. 19, 267–273.10.1080/09513590400018108Search in Google Scholar
Kornhuber, J., Rhein, C., Müller, C.P., and Mühle, C. (2015). Secretory sphingomyelinase in health and disease. Biol. Chem. 396, 707–736.10.1515/hsz-2015-0109Search in Google Scholar
Kott, M., Elke, G., Reinicke, M., Winoto-Morbach, S., Schädler, D., Zick, G., Frerichs, I., Weiler, N., and Schütze, S. (2014). Acid sphingomyelinase serum activity predicts mortality in intensive care unit patients after systemic inflammation: a prospective cohort study. PLoS One 9, e112323.10.1371/journal.pone.0112323Search in Google Scholar
Krauss, T., Azab, H., Dietrich, M., and Augustin, H.G. (1998). Fetal plasma levels of circulating endothelial cell adhesion molecules in normal and preeclamptic pregnancies. Eur. J. Obstet. Gynecol. Reprod. Biol. 78, 41–45.10.1016/S0301-2115(98)00010-4Search in Google Scholar
Kuc, S., Wortelboer, E.J., van Rijn, B.B., Franx, A., Visser, G.H.A., and Schielen, P.C.J.I. (2011). Evaluation of 7 serum biomarkers and uterine artery doppler ultrasound for first-trimester prediction of preeclampsia: a systematic review. Obstet. Gynecol. Surv. 66, 225–239.10.1097/OGX.0b013e3182227027Search in Google Scholar PubMed
Lang, P.A., Schenck, M., Nicolay, J.P., Becker, J.U., Kempe, D.S., Lupescu, A., Koka, S., Eisele, K., Klarl, B.A., Rübben, H., et al. (2007). Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat. Med. 13, 164–170.10.1038/nm1539Search in Google Scholar PubMed
Lansmann, S., Schuette, C.G., Bartelsen, O., Hoernschemeyer, J., Linke, T., Weisgerber, J., and Sandhoff, K. (2003). Human acid sphingomyelinase. Eur. J. Biochem. 270, 1076–1088.10.1046/j.1432-1033.2003.03435.xSearch in Google Scholar PubMed
Levine, R.J., Lam, C., Qian, C., Yu, K.F., Maynard, S.E., Sachs, B.P., Sibai, B.M., Epstein, F.H., Romero, R., Thadhani, R., et al. (2006). Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N. Engl. J. Med. 355, 992–1005.10.1056/NEJMoa055352Search in Google Scholar PubMed
Li, P.-L. and Zhang, Y. (2013). Cross talk between ceramide and redox signaling: Implications for endothelial dysfunction and renal disease. Handb. Exp. Pharmacol. 216, 171–197.10.1007/978-3-7091-1511-4_9Search in Google Scholar PubMed PubMed Central
Llurba, E., Gratacós, E., Martín-Gallán, P., Cabero, L., and Domínguez, C. (2004). A comprehensive study of oxidative stress and antioxidant status in preeclampsia and normal pregnancy. Free Radic. Biol. Med. 37, 557–570.10.1016/j.freeradbiomed.2004.04.035Search in Google Scholar PubMed
Marathe, S., Schissel, S.L., Yellin, M.J., Beatini, N., Mintzer, R., Williams, K.J., and Tabas, I. (1998). Human vascular endothelial cells are a rich and regulatable source of secretory sphingomyelinase. implications for early atherogenesis and ceramide-mediated cell signaling. J. Biol. Chem. 273, 4081–4088.10.1074/jbc.273.7.4081Search in Google Scholar PubMed
Matthiesen, L., Berg, G., Ernerudh, J., Ekerfelt, C., Jonsson, Y., and Sharma, S. (2005). Immunology of preeclampsia. Chem. Immunol. Allergy 89, 49–61.10.1159/000087912Search in Google Scholar PubMed
Maynard, S.E., Min, J.-Y., Merchan, J., Lim, K.-H., Li, J., Mondal, S., Libermann, T.A., Morgan, J.P., Sellke, F.W., Stillman, I.E., et al. (2003). Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111, 649–658.10.1172/JCI17189Search in Google Scholar PubMed PubMed Central
Melland-Smith, M., Ermini, L., Chauvin, S., Craig-Barnes, H., Tagliaferro, A., Todros, T., Post, M., and Caniggia, I. (2015). Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia. Autophagy 11, 653–669.10.1080/15548627.2015.1034414Search in Google Scholar PubMed PubMed Central
Molvarec, A., Szarka, A., Walentin, S., Beko, G., Karádi, I., Prohászka, Z., and Rigó, J., Jr (2011). Serum leptin levels in relation to circulating cytokines, chemokines, adhesion molecules and angiogenic factors in normal pregnancy and preeclampsia. Reprod. Biol. Endocrinol. 9, 124.10.1186/1477-7827-9-124Search in Google Scholar
Mutter, W.P. and Karumanchi, S.A. (2008). Molecular mechanisms of preeclampsia. Microvasc. Res. 75, 1–8.10.1016/j.mvr.2007.04.009Search in Google Scholar
Mühle, C., Huttner, H.B., Walter, S., Reichel, M., Canneva, F., Lewczuk, P., Gulbins, E., and Kornhuber, J. (2013). Characterization of acid sphingomyelinase activity in human cerebrospinal fluid. PLoS One 8, e62912.10.1371/journal.pone.0062912Search in Google Scholar
Opreanu, M., Lydic, T.A., Reid, G.E., McSorley, K.M., Esselman, W.J., and Busik, J.V. (2010). Inhibition of cytokine signaling in human retinal endothelial cells through downregulation of sphingomyelinases by docosahexaenoic acid. Invest. Ophthalmol. Vis. Sci. 51, 3253–3263.10.1167/iovs.09-4731Search in Google Scholar
Pacurari, M., Kafoury, R., Tchounwou, P.B., and Ndebele, K. (2014). The renin-angiotensin-aldosterone system in vascular inflammation and remodeling. Int. J. Inflam. 2014, article ID 689360.10.1155/2014/689360Search in Google Scholar
Patschan, S., Chen, J., Polotskaia, A., Mendelev, N., Cheng, J., Patschan, D., and Goligorsky, M.S. (2008). Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 294, H1119–H1129.10.1152/ajpheart.00713.2007Search in Google Scholar
R Core Team (2013). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http://www.R-project.org/.Search in Google Scholar
Redman, C.W.G. and Sargent, I.L. (2010). Immunology of pre-eclampsia. Am. J. Reprod. Immunol. 63, 534–543.10.1111/j.1600-0897.2010.00831.xSearch in Google Scholar
Redman, C.W., Sacks, G.P., and Sargent, I.L. (1999). Preeclampsia: An excessive maternal inflammatory response to pregnancy. Am. J. Obstet. Gynecol. 180, 499–506.10.1016/S0002-9378(99)70239-5Search in Google Scholar
Reichel, M., Beck, J., Mühle, C., Rotter, A., Bleich, S., Gulbins, E., and Kornhuber, J. (2011). Activity of secretory sphingomyelinase is increased in plasma of alcohol-dependent patients. Alcohol Clin. Exp. Res. 35, 1852–1859.10.1111/j.1530-0277.2011.01529.xSearch in Google Scholar PubMed
Robinson, C.J. and Johnson, D.D. (2007). Soluble endoglin as a second-trimester marker for preeclampsia. Am. J. Obstet. Gynecol. 197, e1–e5.10.1016/j.ajog.2007.03.058Search in Google Scholar PubMed
Schissel, S.L., Keesler, G.A., Schuchman, E.H., Williams, K.J., and Tabas, I. (1998). The cellular trafficking and zinc dependence of secretory and lysosomal sphingomyelinase, two products of the acid sphingomyelinase gene. J. Biol. Chem. 273, 18250–18259.10.1074/jbc.273.29.18250Search in Google Scholar
Sibai, B., Dekker, G. and Kupferminc, M. (2005). Pre-eclampsia. Lancet. 365, 785–799.10.1016/S0140-6736(05)17987-2Search in Google Scholar
Siddiqui, I. (2014). Maternal serum lipids in women with pre-eclampsia. Ann. Med. Health Sci. Res. 4, 638–641.10.4103/2141-9248.139358Search in Google Scholar
Simons, K. and Ikonen, E. (1997). Functional rafts in cell membranes. Nature 387, 569–572.10.1038/42408Search in Google Scholar
Singh, A.T., Dharmarajan, A., Aye, I.L.M.H., and Keelan, J.A. (2012). Ceramide biosynthesis and metabolism in trophoblast syncytialization. Mol. Cell. Endocrinol. 362, 48–59.10.1016/j.mce.2012.05.009Search in Google Scholar
Smith, E.L. and Schuchman, E.H. (2008). The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases. FASEB J. 22, 3419–3431.10.1096/fj.08-108043Search in Google Scholar
Spence, M.W., Byers, D.M., Palmer, F.B., and Cook, H.W. (1989). A new Zn2+-stimulated sphingomyelinase in fetal bovine serum. J. Biol. Chem. 264, 5358–5363.10.1016/S0021-9258(18)83553-0Search in Google Scholar
Spijkers, L.J.A., van den Akker, R.F.P., Janssen, B.J.A., Debets, J.J., De Mey, J.G.R., Stroes, E.S.G., van den Born, B.-J.H., Wijesinghe, D.S., Chalfant, C.E., MacAleese, L., et al. (2011). Hypertension is associated with marked alterations in sphingolipid biology: A potential role for ceramide. PLoS One 6, e21817.10.1371/journal.pone.0021817Search in Google Scholar
Steegers, E.A.P., von Dadelszen, P., Duvekot, J.J., and Pijnenborg, R. (2010). Pre-eclampsia. Lancet 376, 631–644.10.1016/S0140-6736(10)60279-6Search in Google Scholar
Stergiotou, I., Crispi, F., Valenzuela-Alcaraz, B., Bijnens, B., and Gratacós, E. (2013). Patterns of maternal vascular remodeling and responsiveness in early- versus late-onset preeclampsia. Am. J. Obstet. Gynecol. 209, 558.e1–e14.10.1016/j.ajog.2013.07.030Search in Google Scholar PubMed
Uhlén, M., Fagerberg, L., Hallström, B.M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, A., Kampf, C., Sjöstedt, E., Asplund, A., et al. (2015). Proteomics. Tissue-based map of the human proteome. Science 347, 1260419.Search in Google Scholar
Valensise, H., Vasapollo, B., Gagliardi, G., and Novelli, G.P. (2008). Early and late preeclampsia: two different maternal hemodynamic states in the latent phase of the disease. Hypertension 52, 873–880.10.1161/HYPERTENSIONAHA.108.117358Search in Google Scholar PubMed
Venable, M.E. and Yin, X. (2009). Ceramide induces endothelial cell senescence. Cell. Biochem. Funct. 27, 547–551.10.1002/cbf.1605Search in Google Scholar PubMed
Warrington, J.P., George, E.M., Palei, A.C., Spradley, F.T., and Granger, J.P. (2013). Recent advances in the understanding of the pathophysiology of preeclampsia. Hypertension 62, 666–673.10.1161/HYPERTENSIONAHA.113.00588Search in Google Scholar PubMed PubMed Central
Wong, M.L., Xie, B., Beatini, N., Phu, P., Marathe, S., Johns, A., Gold, P.W., Hirsch, E., Williams, K.J., Licinio, J., et al. (2000). Acute systemic inflammation up-regulates secretory sphingomyelinase in vivo: a possible link between inflammatory cytokines and atherogenesis. Proc. Natl. Acad. Sci. USA 97, 8681–8686.10.1073/pnas.150098097Search in Google Scholar PubMed PubMed Central
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