Differentially-expressed genes associated with glycophosphatidylinositol (GPI)-anchored proteins by diabetes-related toxic substances in human endothelial cells


Glycophosphatidylinositol (GPI)-anchored proteins are one of the membrane-bound proteins that have diverse functions. There have been some reports that their expression or activities are altered in diabetes. Many proteins, including GPI-anchored proteins, lose their biological function secondary to carbonylation in diabetes. Carbonylation causes oxidative damage of numerous proteins in the human body. Diabetic complications are related to carbonyl adducts in vascular tissue. Therefore, we examined whether carbonyl compounds associated with diabetes affect the expression of GPI-related genes in human umbilical vein endothelial cells (HUVECs). Among the more than 150 GPI anchor-related genes investigated, 54 genes were up-regulated by more than 2-fold, while 31 genes were down-regulated with altered expression levels of 2-fold in acrolein (ACR)-treated cells. The majority of the genes changed by ACR involved GPI anchor biosynthesis. Crotonaldehyde and methylglyoxal altered a few genes encoding GPI-anchored proteins. According to their functional characteristics, genes were classified into the Gene Ontology functional categories. We also identified the distribution of functional groups of GPI anchor-related genes in HUVECs. In conclusion, our data suggest that these reactive carbonyl compounds modulate GPI anchor-related gene expression, which may have a role in diabetic vasculopathy.

This is a preview of subscription content, access via your institution.


  1. 1.

    Orlean, P. & Menon, A.K. GPI anchoring of protein in yeast and mammalian cells, or: how we learned to stop worrying and love glycophospholipids. J. Lipid Res. 48, 993–1011 (2007).

    Article  CAS  Google Scholar 

  2. 2.

    Lisanti, M.P., Rodriguez-Boulan, E. & Saltiel, A.R. Emerging functional roles for the glycosyl-phosphatidylinositol membrane protein anchor. J. Membr. Biol. 117, 1–10 (1990).

    Article  CAS  Google Scholar 

  3. 3.

    Hazenbos, W.L., Wu, P., Eastham-Anderson, J., Kinoshita, T. & Brown, E.J. Impaired FcepsilonRI stability, signaling, and effector functions in murine mast cells lacking glycosylphosphatidylinositol-anchored proteins. Blood 118, 4377–4383 (2011).

    Article  CAS  Google Scholar 

  4. 4.

    Murata, D. et al. GPI-anchor synthesis is indispensable for the germline development of the nematode Caenorhabditis elegans. Mol. Biol. Cell 23, 982–995 (2012).

    Article  CAS  Google Scholar 

  5. 5.

    Leidich, S.D., Drapp, D.A. & Orlean, P. A conditionally lethal yeast mutant blocked at the first step in glycosyl phosphatidylinositol anchor synthesis. J. Biol. Chem. 269, 10193–10196 (1994).

    CAS  Google Scholar 

  6. 6.

    Kawagoe, K. et al. Glycosylphosphatidylinositol-anchordeficient mice: implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria. Blood 87, 3600–3606 (1996).

    CAS  Google Scholar 

  7. 7.

    Nozaki, M. et al. Developmental abnormalities of glycosylphosphatidylinositolanchor-deficient embryos revealed by Cre/loxP system. Lab. Invest. 79, 293–299 (1999).

    CAS  Google Scholar 

  8. 8.

    Nagamune, K. et al. Critical roles of glycosylphosphatidylinositol for Trypanosoma brucei. Proc. Natl. Acad. Sci. USA 97, 10336–10341 (2000).

    Article  CAS  Google Scholar 

  9. 9.

    Gillmor, C.S. et al. Glycosylphosphatidylinositol-anchored proteins are required for cell wall synthesis and morphogenesis in Arabidopsis. Plant Cell 17, 1128–1140 (2005).

    Article  CAS  Google Scholar 

  10. 10.

    Ueda, Y. et al. PGAP1 knock-out mice show otocephaly and male infertility. J. Bio. Chem. 282, 30373–30380 (2007).

    Article  CAS  Google Scholar 

  11. 11.

    Karnieli, E., Armoni, M., Cohen, P., Kanter, Y. & Rafaeloff, R. Reversal of insulin resistance in diabetic rat adipocytes by insulin therapy. Restoration of pool of glucose transporters and enhancement of glucosetransport activity. Diabetes 36, 925–931 (1987).

    Article  CAS  Google Scholar 

  12. 12.

    Skillen, A.W., Hawthorne, G.C. & Turner, G.A. Serum alkaline phosphatase in rats with streptozotocin-induced diabetes. Horm. Metab. Res. 19, 505–506 (1987).

    Article  CAS  Google Scholar 

  13. 13.

    Acosta, J. et al. Molecular basis for a link between complement and the vascular complications of diabetes. Proc. Natl. Acad. Sci. USA 97, 5450–5455 (2000).

    Article  CAS  Google Scholar 

  14. 14.

    Vlassara, H. Recent progress in advanced glycation end products and diabetic complications. Diabetes 46, S19-25 (1997).

    Google Scholar 

  15. 15.

    Hotta, N. New approaches for treatment in diabetes: aldose reductase inhibitors. Biomed. Pharmacother. 49, 232–243 (1995).

    Article  CAS  Google Scholar 

  16. 16.

    Lapolla, A. & Fedele, D. [Oxidative stress and diabetes: role in the development of chronic complications]. Minerva Endocrinol. 18, 99–108 (1993).

    CAS  Google Scholar 

  17. 17.

    Kennedy, A.L. & Lyons, T.J. Glycation, oxidation, and lipoxidation in the development of diabetic complications. Metabolism 46, 14–21 (1997).

    Article  CAS  Google Scholar 

  18. 18.

    Witztum, J.L. Role of modified lipoproteins in diabetic macroangiopathy. Diabetes 46, S112–114 (1997).

    CAS  Google Scholar 

  19. 19.

    Ishii, H., Koya, D. & King, G.L. Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. J. Mol. Med. (Berl) 76, 21–31 (1998).

    Article  CAS  Google Scholar 

  20. 20.

    Chiarelli, F., Santilli, F. & Mohn, A. Role of growth factors in the development of diabetic complications. Horm. Res. 53, 53–67 (2000).

    Article  CAS  Google Scholar 

  21. 21.

    Thomson, S.E., McLennan, S.V. & Twigg, S.M. Growth factors in diabetic complications. Expert Rev. Clin. Immunol. 2, 403–418 (2006).

    Article  CAS  Google Scholar 

  22. 22.

    Baynes, J.W. Role of oxidative stress in development of complications in diabetes. Diabetes 40, 405–412 (1991).

    Article  CAS  Google Scholar 

  23. 23.

    McLellan, A.C., Thornalley, P.J., Benn, J. & Sonksen, P.H. Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications. Clin. Sci. (Lond) 87, 21–29 (1994).

    CAS  Google Scholar 

  24. 24.

    Berlanga, J. et al. Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds. Clin. Sci. 109, 83–95 (2005).

    Article  CAS  Google Scholar 

  25. 25.

    Ramasamy, R., Yan, S.F. & Schmidt, A.M. Methylglyoxal comes of AGE. Cell 124, 258–260 (2006).

    Article  CAS  Google Scholar 

  26. 26.

    Minko, I.G. et al. Chemistry and biology of DNA containing 1,N(2)-deoxyguanosine adducts of the alpha, beta-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal. Chem. Res. Toxicol. 22, 759–778 (2009).

    Article  CAS  Google Scholar 

  27. 27.

    Medina-Navarro, R., Nieto-Aguilar, R. & Alvares-Aguilar, C. Protein conjugated with aldehydes derived from lipid peroxidation as an independent parameter of the carbonyl stress in the kidney damage. Lipids in Health and Disease 10, 1–7 (2011).

    Article  Google Scholar 

  28. 28.

    Suzuki, D. & Miyata, T. Carbonyl stress in the pathogenesis of diabetic nephropathy. Intern. Med. 38, 309–314 (1999).

    Article  CAS  Google Scholar 

  29. 29.

    Lee, S.E. et al. Differentially-expressed genes related to atherosclerosis in acrolein-stimulated human umbilical vein endothelial cells. BioChip J. 4, 264–271 (2010).

    Article  CAS  Google Scholar 

  30. 30.

    Lee, S.E. et al. Methylglyoxal-mediated alteration of gene expression in human endothelial cells. BioChip J. 5, 220–228 (2011).

    Article  CAS  Google Scholar 

  31. 31.

    Imai, T. et al. DNA microarray analysis of the epithelialmesenchymal transition of mesothelial cells in a rat model of peritoneal dialysis. Adv. Perit. Dial. 27, 11–15 (2011).

    Google Scholar 

  32. 32.

    Jeong, S.I. et al. Genome-wide analysis of gene expression by crotonaldehyde in human umbilical vein endothelial cells. Mol. Cell. Toxicol. 7, 127–134 (2011).

    Article  CAS  Google Scholar 

  33. 33.

    Trevino, V., Falciani, F. & Barrera-Saldana, H.A. DNA microarrays: a powerful genomic tool for biomedical and clinical research. Mol. Med. 13, 527–541 (2007).

    Article  CAS  Google Scholar 

  34. 34.

    Archacki, S.R. & Wang, Q.K. Microarray analysis of cardiovascular diseases. Methods Mol. Med. 129, 1–13 (2006).

    CAS  Google Scholar 

  35. 35.

    Hiltunen, M.O. et al. Changes in gene expression in atherosclerotic plaques analyzed using DNA array. Atherosclerosis 165, 23–32 (2002).

    Article  CAS  Google Scholar 

  36. 36.

    Lee, N.J., Lee, S.E., Lee, S.H., Ryu, D.S. & Park, Y.S. Acrolein induces adaptive response through upregulate of HO-1 via activation of Nrf2 in RAW 264.7 macrophage. Mol. Cell. Toxicol. 5, 230–236 (2009).

    Google Scholar 

  37. 37.

    Thompson, C.A. & Burcham, P.C. Genome-wide transcriptional responses to acrolein. Chem. Res. Toxicol. 21, 2245–2256 (2008).

    Article  CAS  Google Scholar 

  38. 38.

    Kutzman, R.S., Wehner, R.W. & Haber, S.B. The impact of inhaled acrolein on hypertension-sensitive and resistant rats. J. Environ. Pathol. Toxicol. Oncol. 6, 97–108 (1986).

    CAS  Google Scholar 

  39. 39.

    Srivastava, S. et al. Oral exposure to acrolein exacerbates atherosclerosis in apoE-null mice. Atherosclerosis 215, 301–308 (2011).

    Article  CAS  Google Scholar 

  40. 40.

    Orlean, P. & Menon, A.K. Thematic review series: lipid posttranslational modifications. GPI anchoring of protein in yeast and mammalian cells, or: how we learned to stop worrying and love glycophospholipids. J. Lipid Res. 48, 993–1011 (2007).

    Article  CAS  Google Scholar 

  41. 41.

    Yang, H. et al. Up-regulation of heme oxygenase-1 by Korean red ginseng water extract as a cytoprotective effect in human endothelial cells. J. Ginseng Res. 35, 352–359 (2011).

    Article  CAS  Google Scholar 

  42. 42.

    Park, Y.S. et al. Acrolein induces cyclooxygenase-2 and prostaglandin production in human umbilical vein endothelial cells: roles of p38 MAP kinase. Arterioscler. Thromb. Vasc. Biol. 27, 1319–1325 (2007).

    Article  CAS  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Yong Seek Park.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Yang, H., Lee, S.E., Jeong, S.I. et al. Differentially-expressed genes associated with glycophosphatidylinositol (GPI)-anchored proteins by diabetes-related toxic substances in human endothelial cells. BioChip J 6, 262–270 (2012). https://doi.org/10.1007/s13206-012-6309-y

Download citation


  • GPI-anchored protein
  • Diabetes
  • Acrolein
  • Microarray
  • Endothelial cell