, Volume 42, Issue 2, pp 606–617 | Cite as

ApoM-S1P Modulates Ox-LDL-Induced Inflammation Through the PI3K/Akt Signaling Pathway in HUVECs

  • Zhi Zheng
  • Yongzhi Zeng
  • Xiao Zhu
  • Ying Tan
  • Yi Li
  • Qian Li
  • Guanghui YiEmail author


Studies have shown that apolipoprotein M (apoM), the main carrier of sphingosine-1-phosphate (S1P), is closely related to lipid metabolism and inflammation. While there are many studies on apoM and lipid metabolism, little is known about the role of apoM in inflammation. Atherosclerosis is a chronic inflammatory process. To clarify what role apoM plays in atherosclerosis, we used oxidized low-density lipoprotein (ox-LDL) to induce an inflammatory model of atherosclerosis. Our preliminary results indicate that ox-LDL upregulates the expression of S1P receptor 2 (S1PR2) in human umbilical vein endothelial cells (HUVECs). Ox-LDL-induced HUVECs were treated with apoM-bound S1P (apoM-S1P), free S1P or apoM, and apoM-S1P was found to significantly inhibit the expression of inflammatory factors and adhesion molecules. In addition, apoM-S1P inhibits ox-LDL-induced cellular inflammation via S1PR2. Moreover, apoM-S1P induces phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt, preventing nuclear translocation of nuclear factor-κB (NF-κB). PI3K-specific inhibitors and Akt inhibitors suppress apoM-S1P/S1PR2-induced interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) release and affect nuclear translocation of NF-κB. In conclusion, the results demonstrate for the first time that apoM-S1P inhibits ox-LDL-induced inflammation in HUVECs via the S1PR2-mediated PI3K/Akt signaling pathway. This finding may aid in the development of new treatments for atherosclerosis.


apoM-S1P ox-LDL inflammatory factors adhesion molecules atherosclerosis 


Funding Information

The authors sincerely acknowledge the financial assistance provided by the National Natural Science Foundation of China (No. 81770490) and the Construct Program of the Key Discipline in Hunan Province (Basic Medicine Sciences in University of South China).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

10753_2018_918_Fig8_ESM.png (148 kb)
Supplementary Fig. 1

Effect of apoM-albumin on inflammatory factors and adhesion factors induced by ox-LDL in endothelial cells. a Western blotting was used to detect the expression of IL-1β and TNF-α. (PNG 148 kb)

10753_2018_918_MOESM1_ESM.tif (903 kb)
High Resolution Image (TIF 902 kb)
10753_2018_918_Fig9_ESM.png (132 kb)
Supplementary Fig. 2

Effect of different concentrations of apoM-S1P on ox-LDL-induced inflammation of HUVECs. a Western blotting was used to detect the release of ICAM-1 and VCAM-1 in ox-LDL-induced HUVECs by apoM-S1P at different concentrations. * P < 0.05 vs. control group, n = 3. (PNG 131 kb)

10753_2018_918_MOESM2_ESM.tif (665 kb)
High Resolution Image (TIF 665 kb)


  1. 1.
    Borup, A., P.M. Christensen, and L.B. Nielsen. 2015. Apolipoprotein M in lipid metabolism and cardiometabolic diseases. Current Opinion in Lipidology 26: 48–55.CrossRefGoogle Scholar
  2. 2.
    Dahlbäck, B. 2006. Apolipoprotein M--a novel player in high-density lipoprotein metabolism and atherosclerosis. Current Opinion in Lipidology 17: 291–295.CrossRefGoogle Scholar
  3. 3.
    Nádró, B., L. Juhász, A. Szentpéteri, D. Páll, G. Paragh, and M. Harangi. 2018. The role of apolipoprotein M and sphingosine 1-phosphate axis in the prevention of atherosclerosis. Orvosi Hetilap 159: 168–175.CrossRefGoogle Scholar
  4. 4.
    Feingold, K.R., J.K. Shigenaga, L.G. Chui, A. Moser, W. Khovidhunkit, and C. Grunfeld. 2007. Infection and inflammation decrease apolipoprotein M expression. Atherosclerosis 199: 19–26.CrossRefGoogle Scholar
  5. 5.
    Ma, X., Y.W. Hu, Z.L. Zhao, L. Zheng, Y.R. Qiu, J.L. Huang, X.J. Wu, X.R. Mao, J. Yang, J.Y. Zhao, S.F. Li, M.N. Gu, and Q. Wang. 2013. Anti-inflammatory effects of propofol are mediated by apolipoprotein M in a hepatocyte nuclear factor-1a-dependent manner. Archives of Biochemistry and Biophysics 533: 1–10.CrossRefGoogle Scholar
  6. 6.
    Christoffersen, C., M. Jauhiainen, M. Moser, B. Porse, C. Ehnholm, M. Boesl, B. Dahlbäck, and L.B. Nielsen. 2008. Effect of apolipoprotein M on high density lipoprotein metabolism and atherosclerosis in low density lipoprotein receptor knock-out mice. J Biol Chem 283: 1839–1847.CrossRefGoogle Scholar
  7. 7.
    Sevvana, M., J. Ahnström, C. Egerer-Sieber, H.A. Lange, B. Dahlbäck, and Y.A. Muller. 2009. Serendipitous fatty acid binding reveals the structural determinants for ligand recognition in apolipoprotein M. J Biol 393: 920–936.Google Scholar
  8. 8.
    Christoffersen, C., H. binata, S.B. Kumaraswamy, S. Galvani, J. Ahnström, M. Sevvana, C. Egerer-Sieber, Y.A. Muller, and T. Hla. 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.CrossRefGoogle Scholar
  9. 9.
    Pirillo, A., and G.D. Norata. 2013. LOX-1, oxLDL, and atherosclerosis. Mediators of Inflammation 2013: 152786.CrossRefGoogle Scholar
  10. 10.
    Vestri, A., F. Pierucci, A. Frati, L. Monaco, and E. Meacci. 2017. Sphingosine 1-phosphate receptors: Do they have a therapeutic potential in cardiac fibrosis? Frontiers in Pharmacology 8: 296.CrossRefGoogle Scholar
  11. 11.
    Lai, W.Q., F.L. Chia, and B.P. Leung. 2012. Sphingosine kinase and sphingosine-1-phosphate receptors: Novel therapeutic targets of rheumatoid arthritis? Future Medicinal Chemistry 4: 727–733.CrossRefGoogle Scholar
  12. 12.
    Liu, H., H. Jin, X. Yue, J. Han, P. Baum, D.R. Abendschein, and Z. Tu. 2017. PET study of sphingosine-1-phosphate receptor 1 expression in response to vascular inflammation in a rat model of carotid injury. Molecular Imaging 6: 1536012116689770.Google Scholar
  13. 13.
    Miraghazadeh, B., and M.C. Cook. 2018. Nuclear factor-kappaB in autoimmunity: Man and mouse. Frontiers in Immunology 9: 613.CrossRefGoogle Scholar
  14. 14.
    Johnston, T.P. 2009. Poloxamer 407 increases soluble adhesion molecules, ICAM-1, VCAM-1 and E-selectin, in C57BL/6 mice. The Journal of Pharmacy and Pharmacology 61: 1681–1688.Google Scholar
  15. 15.
    Pyne, N.J., M. McNaughton, S. Boomkamp, N. MacRitchie, C. Evangelisti, A.M. Martelli, H.R. Jiang, S. Ubhi, and S. Pyne. 2016. Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation. Advances in Biological Regulation 60: 151–159.CrossRefGoogle Scholar
  16. 16.
    Ren, K., Y.J. Lu, Z.C. Mo, X. Liu, Z.L. Tang, Y. Jiang, X.S. Peng, L. Li, Q.H. Zhang, and G.H. Yi. 2017. ApoA-I/SR-BI modulates S1P/S1PR2-mediated inflammation through the PI3K/Akt signaling pathway in HUVECs. Journal of Physiology and Biochemistry 73: 287–296.CrossRefGoogle Scholar
  17. 17.
    Hamed, S. 2006. Endothelial progenitor cells and atherosclerosis. Harefuah 145: 358–361.Google Scholar
  18. 18.
    Berliner, J.A., and J.W. Heinecke. 1996. The role of oxidized lipoproteins in atherosclerosis. Free Radical Biology & Medicine 20: 707–727.CrossRefGoogle Scholar
  19. 19.
    Obinata, H. 2012. Sphingosine 1-phosphate in coagulation and inflammation. Seminars in Immunopathology 34: 73–91.CrossRefGoogle Scholar
  20. 20.
    Du, J., C. Zeng, Q. Li, B. Chen, H. Liu, X. Huang, and Q. Huang. 2012. LPS and TNF-α induce expression of sphingosine-1-phosphate receptor-2 in human microvascular endothelial cells. Pathology, Research and Practice 208: 82–88.CrossRefGoogle Scholar
  21. 21.
    Kosmas, C.E., I. Martinez, A. Sourlas, K.V. Bouza, F.N. Campos, V. Torres, P.D. Montan, and E. Guzman. 2018. High-density lipoprotein (HDL) functionality and its relevance to atherosclerotic cardiovascular disease. Drugs Context 7: 212525.Google Scholar
  22. 22.
    Hait, N.C., C.A. Oskeritzian, S.W. Paugh, S. Milstien, and S. Spiegel. 2006. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochimica et Biophysica Acta 1758: 2016–2026.CrossRefGoogle Scholar
  23. 23.
    Książek, M., M. Chacińska, A. Chabowski, and M. Baranowski. 2015. Sources, metabolism, and regulation of circulating sphingosine-1-phosphate. Journal of Lipid Research 56: 1271–1281.CrossRefGoogle Scholar
  24. 24.
    Spiegel, S., and S. Milstien. 2003. Sphingosine-1-phosphate: An enigmatic signalling lipid. Nature Reviews. Molecular Cell Biology 4: 397–407.CrossRefGoogle Scholar
  25. 25.
    Luo, G., X. Zhang, and P. Nilsson-Ehle. 2004. Apolipoprotein M. Lipids in Health and Disease 3: 21.CrossRefGoogle Scholar
  26. 26.
    Kurano, M., K. Tsuneyama, Y. Morimoto, T. Shimizu, M. Jona, H. Kassai, K. Nakao, A. Aiba, and Y. Yatomi. 2018. Apolipoprotein M protects lipopolysaccharide-treated mice from death and organ injury. Thrombosis and Haemostasis 118: 1021–1035.CrossRefGoogle Scholar
  27. 27.
    Jiang, Y., L.L. Jiang, X.M. Maimaitirexiati, Y. Zhang, and L. Wu. 2015. Irbesartan attenuates TNF-α-induced ICAM-1, VCAM-1, and E-selectin expression through suppression of NF-κB pathway in HUVECs. European Review for Medical and Pharmacological Sciences 19: 3295–3302.Google Scholar
  28. 28.
    Osborn, L., C. Hession, R. Tizard, C. Vassallo, S. Luhowskyj, G. Chi-Rosso, and R. Lobb. 1989. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 59: 1203–1211.CrossRefGoogle Scholar
  29. 29.
    Takuwa, Y., Y. Okamoto, and K. Yoshioka. 2012. Sphingosine-1-phosphate signaling in physiology and diseases. Biofactors 38: 329–337.CrossRefGoogle Scholar
  30. 30.
    Brown, J.D., C.Y. Lin, Q. Duan, G. Griffin, A. Federation, R.M. Paranal, S. Bair, G. Newton, A. Lichtman, A. Kung, T. Yang, and H. Wang. 2014. NF-kappaB directs dynamic super enhancer formation in inflammation and atherogenesis. Molecular Cell 56: 219–231.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan ProvinceUniversity of South ChinaHengyangChina

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