Skip to main content

Advertisement

SpringerLink
Log in

High Mobility Group Box 1 (HMGB1) Mediates High-Glucose-Induced Calcification in Vascular Smooth Muscle Cells of Saphenous Veins

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Diabetes accelerates saphenous vein grafts calcification after years of coronary artery bypass grafting (CABG) surgery. Vascular smooth muscle cells (VSMC) undergoing a phenotypic switch to osteoblast-like cells play a key role in this process. The receptor for advanced glycation and products (RAGE) and toll-like receptors (TLRs) are all involved in various cardiovascular calcification processes. Therefore, the role of their common ligand, high mobility group box 1 (HMGB1), in high-glucose-induced calcification in VSMC of saphenous vein was investigated. In this study, VSMC were cultured from saphenous vein of patients arranged for CABG. We first demonstrated high-glucose-induced HMGB1 translocation from nucleus to cytosol, and this translocation was induced through a NADPH oxidase and PKC-dependent pathway. We next found high glucose also increased TLR2, TLR4, and RAGE expression. Then, we revealed downregulating HMGB1 expression abolished high-glucose-induced calcification accompanied by NFκB inactivation and low expression of bone morphogenetic protein-2 (BMP-2). We further demonstrated NFκB activation was necessary in high-glucose-induced BMP-2 expression and calcification. Finally, by using a chromatin immunoprecipitation assay, we demonstrated NFκB transcriptional regulation of BMP-2 promoter was induced by NFκB binding to its κB element on the BMP-2 promoter. Our findings thus suggest HMGB1 plays an important role in mediating the calcification process induced by high glucose through NFκB activation and BMP-2 expression in VSMC of saphenous vein.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig 1
Fig 2
Fig 3
Fig 4
Fig 5
Fig 6
Fig 7

Similar content being viewed by others

REFERENCES

  1. Wittlinger, T., I. Martinovic, F. Bakhtiary, F. Oezaslan, A. Moritz, and K. Ehrhard. 2006. Detection of vein graft disease using 4-row computed tomography. Evaluation of coronary bypass graft patency and correlation with the Ca-score. The Journal of Thoracic and Cardiovascular Surgery 54: 96–101.

    Article  CAS  Google Scholar 

  2. Peykar, S., D.J. Angiolillo, T.A. Bass, and M.A. Costa. 2004. Saphenous vein graft disease. Minerva Cardioangiologica 52: 379–390.

    PubMed  CAS  Google Scholar 

  3. Castagna, M.T., G.S. Mintz, P. Ohlmann, J. Kotani, A. Maehara, N. Gevorkian, E. Cheneau, E. Stabile, A.E. Ajani, W.O. Suddath, K.M. Kent, L.F. Satler, A.D. Pichard, and N.J. Weissman. 2005. Incidence, location, magnitude, and clinical correlates of saphenous vein graft calcification: An intravascular ultrasound and angiographic study. Circulation 111: 1148–1152.

    Article  PubMed  CAS  Google Scholar 

  4. Ndip, A., A. Williams, E.B. Jude, F. Serracino-Inglott, S. Richardson, J.V. Smyth, A.J. Boulton, and M.Y. Alexander. 2011. The RANKL/RANK/OPG signaling pathway mediates medial arterial calcification in diabetic Charcot neuroarthropathy. Diabetes 60: 2187–2196.

    Article  PubMed  CAS  Google Scholar 

  5. Johnson, R.C., J.A. Leopold, and J. Loscalzo. 2006. Vascular calcification: pathobiological mechanisms and clinical implications. Circulation Research 99: 1044–1059.

    Article  PubMed  CAS  Google Scholar 

  6. Chen, N.X., D. Duan, K.D. O'Neill, and S.M. Moe. 2006. High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells. Nephrology, Dialysis, Transplantation 21: 3435–3442.

    Article  PubMed  CAS  Google Scholar 

  7. Liu, F., H. Zhong, J.Y. Liang, P. Fu, Z.J. Luo, L. Zhou, R. Gou, and J. Huang. 2010. Effect of high glucose levels on the calcification of vascular smooth muscle cells by inducing osteoblastic differentiation and intracellular calcium deposition via BMP-2/Cbfα-1 pathway. Journal of Zhejiang University. Science. B 11: 905–911.

    Article  PubMed  CAS  Google Scholar 

  8. Hsieh, M.S., W.B. Zhong, S.C. Yu, J.Y. Lin, W.M. Chi, and H.M. Lee. 2010. Dipyridamole suppresses high glucose-induced osteopontin secretion and mRNA expression in rat aortic smooth muscle cells. Circulation Journal 74: 1242–1250.

    Article  PubMed  CAS  Google Scholar 

  9. New, S.E., and E. Aikawa. 2011. Cardiovascular calcification: an inflammatory disease. Circulation Journal 75: 1305–1313.

    Article  PubMed  CAS  Google Scholar 

  10. Dasu, M.R., S. Devaraj, L. Zhao, D.H. Hwang, and I. Jialal. 2008. High glucose induces toll-like receptor expression in human monocytes: mechanism of activation. Diabetes 57: 3090–3098.

    Article  PubMed  CAS  Google Scholar 

  11. Thornalley, P.J. 2007. Dietary AGEs and ALEs and risk to human health by their interaction with the receptor for advanced glycation endproducts (RAGE)—An introduction. Molecular Nutrition & Food Research 51: 1107–1110.

    Article  CAS  Google Scholar 

  12. Heizmann, C.W. 2007. The mechanism by which dietary AGEs are a risk to human health is via their interaction with RAGE: Arguing against the motion. Molecular Nutrition & Food Research 51: 1116–1119.

    Article  CAS  Google Scholar 

  13. Naruse, K., T. Sado, T. Noguchi, T. Tsunemi, S. Yoshida, J. Akasaka, N. Koike, H. Oi, and H. Kobayashi. 2012. Peripheral RAGE (receptor for advanced glycation endproducts)-ligands in normal pregnancy and preeclampsia: Novel markers of inflammatory response. Journal of Reproductive Immunology 93: 69–74.

    Article  PubMed  CAS  Google Scholar 

  14. Cai, X.Y., L. Lu, Y.N. Wang, C. Jin, R.Y. Zhang, Q. Zhang, Q.J. Chen, and W.F. Shen. 2011. Association of increased S100B, S100A6 and S100P in serum levels with acute coronary syndrome and also with the severity of myocardial infarction in cardiac tissue of rat models with ischemia–reperfusion injury. Atherosclerosis 217: 536–542.

    Article  PubMed  CAS  Google Scholar 

  15. Hofmann Bowman, M.A., J. Gawdzik, U. Bukhari, A.N. Husain, P.T. Toth, G. Kim, J. Earley, and E.M. McNally. 2011. S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E-null mice by activating an osteogenic gene regulatory program. Arteriosclerosis, Thrombosis, and Vascular Biology 31: 337–344.

    Article  PubMed  CAS  Google Scholar 

  16. Harris, H.E., U. Andersson, and D.S. Pisetsky. 2012. HMGB1: A multifunctional alarmin driving autoimmune and inflammatory disease. Nature Review Rheumatology 8: 195–202.

    Article  CAS  Google Scholar 

  17. Sims, G.P., D.C. Rowe, S.T. Rietdijk, R. Herbst, and A.J. Coyle. 2010. HMGB1 and RAGE in inflammation and cancer. Annual Review of Immunology 28: 367–388.

    Article  PubMed  CAS  Google Scholar 

  18. Csiszar, A., K.E. Smith, A. Koller, G. Kaley, J.G. Edwards, and Z. Ungvari. 2005. Regulation of bone morphogenetic protein-2 expression in endothelial cells: Role of nuclear factor-kappaB activation by tumor necrosis factor-alpha, H2O2, and high intravascular pressure. Circulation 111: 2364–2372.

    Article  PubMed  CAS  Google Scholar 

  19. Lee, T.S., K.A. Saltsman, H. Ohashi, and G.L. King. 1989. Activation of protein kinase C by elevation of glucose concentration: Proposal for a mechanism in the development of diabetic vascular complications. Proceedings of the National Academy of Sciences of the United States of America 86: 5141–5.

    Article  PubMed  CAS  Google Scholar 

  20. Inoguchi, T., P. Li, F. Umeda, H.Y. Yu, M. Kakimoto, M. Imamura, T. Aoki, T. Etoh, T. Hashimoto, M. Naruse, H. Sano, H. Utsumi, and H. Nawata. 2000. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49: 1939–45.

    Article  PubMed  CAS  Google Scholar 

  21. Peters, K.R. 2011. Intensifying treatment of type 2 diabetes mellitus: Adding insulin. Pharmacotherapy 31(12 Suppl): 54S–64S.

    Article  PubMed  CAS  Google Scholar 

  22. Nelson, S.E., and P.J. Palumbo. 2006. Addition of insulin to oral therapy in patients with type 2. Diabetes 331: 257–263.

    Google Scholar 

  23. Tanenberg, R.J. 2004. Transitioning pharmacologic therapy from oral agents to insulin for type 2 diabetes. Current Medical Research and Opinion 20: 541–553.

    Article  PubMed  Google Scholar 

  24. Towler, D.A. 2011. Vascular calcification: It's all the RAGE! Arteriosclerosis, Thrombosis, and Vascular Biology 31: 237–239.

    Article  PubMed  CAS  Google Scholar 

  25. Gawdzik, J., L. Mathew, G. Kim, T.S. Puri, and M.A. Hofmann Bowman. 2011. Vascular remodeling and arterial calcification are directly mediated by S100A12 (EN-RAGE) in chronic kidney disease. American Journal of Nephrology 33: 250–259.

    Article  PubMed  CAS  Google Scholar 

  26. Yao, D., and M. Brownlee. 2010. Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes 59: 249–255.

    Article  PubMed  CAS  Google Scholar 

  27. Soro-Paavonen, A.M. Watson, J. Li, K. Paavonen, A. Koitka, A.C. Calkin, D. Barit, M.T. Coughlan, B.G. Drew, G.I. Lancaster, M. Thomas, J.M. Forbes, P.P. Nawroth, A. Bierhaus, M.E. Cooper, and K.A. Jandeleit-Dahm. 2008. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes 57: 2461–2469.

    Article  PubMed  CAS  Google Scholar 

  28. López, J., I. Fernández-Pisonero, A.I. Dueñas, P. Maeso, J.A. Román, M.S. Crespo, and C. García-Rodríguez. 2012. Viral and bacterial patterns induce TLR-mediated sustained inflammation and calcification in aortic valve interstitial cells. International Journal of Cardiology 158: 18–25.

    Article  PubMed  Google Scholar 

  29. Su, X., L. Ao, Y. Shi, T.R. Johnson, D.A. Fullerton, and X. Meng. 2011. Oxidized low density lipoprotein induces bone morphogenetic protein-2 in coronary artery endothelial cells via Toll-like receptors 2 and 4. The Journal of Biology Chemistry 286: 12213–12220.

    Article  CAS  Google Scholar 

  30. Zhao, M.M., M.J. Xu, Y. Cai, G. Zhao, Y. Guan, W. Kong, C. Tang, and X. Wang. 2011. Mitochondrial reactive oxygen species promote p65 nuclear translocation mediating high-phosphate-induced vascular calcification in vitro and in vivo. Kidney International 79: 1071–1079.

    Article  PubMed  CAS  Google Scholar 

  31. Volz, H.C., C. Seidel, D. Laohachewin, Z. Kaya, O.J. Müller, S.T. Pleger, F. Lasitschka, M.E. Bianchi, A. Remppis, A. Bierhaus, H.A. Katus, and M. Andrassy. 2010. HMGB1: The missing link between diabetes mellitus and heart failure. Basic Research in Cardiology 105: 805–820.

    Article  PubMed  CAS  Google Scholar 

  32. Hattori, Y., S. Hattori, N. Sato, and K. Kasai. 2000. High-glucose-induced nuclear factor kappaB activation in vascular smooth muscle cells. Cardiovascular Research 46: 188–197.

    Article  PubMed  CAS  Google Scholar 

  33. Kim, Y.S., J.S. Kim, J.S. Kwon, M.H. Jeong, J.G. Cho, J.C. Park, J.C. Kang, and Y. Ahn. 2010. BAY 11–7082, a nuclear factor-κB inhibitor, reduces inflammation and apoptosis in a rat cardiac ischemia–reperfusion injury model. International Heart Journal 51: 348–353.

    Article  PubMed  CAS  Google Scholar 

  34. Tranter, M., X. Ren, T. Forde, M.E. Wilhide, J. Chen, M.A. Sartor, M. Medvedovic, and W.K. Jones. 2010. NF-kappaB driven cardioprotective gene programs; Hsp70.3 and cardioprotection after late ischemic preconditioning. Journal of Molecular and Cellular Cardiology 49: 664–72.

    Article  PubMed  CAS  Google Scholar 

  35. Xuan, Y.T., X.L. Tang, S. Banerjee, H. Takano, R.C. Li, H. Han, Y. Qiu, J.J. Li, and R. Bolli. 1999. Nuclear factor-kappaB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circulation Research 84: 1095–109.

    Article  PubMed  CAS  Google Scholar 

  36. Feng, J.Q., L. Xing, J.H. Zhang, M. Zhao, D. Horn, J. Chan, B.F. Boyce, S.E. Harris, G.R. Mundy, and D. Chen. 2003. NF-kappaB specifically activates BMP-2 gene expression in growth plate chondrocytes in vivo and in a chondrocyte cell line in vitro. The Journal of Biology Chemistry 278: 29130–29135.

    Article  CAS  Google Scholar 

  37. Li, X., and X.Z. Bai. 2008. NF-kappaB modulates activation of the BMP-2 gene by trichostatin A. Molecular Biology (Mosk) 42: 990–996.

    CAS  Google Scholar 

  38. Graham, T.R., V.A. Odero-Marah, L.W. Chung, K.C. Agrawal, R. Davis, and A.B. Abdel-Mageed. 2009. PI3K/Akt-dependent transcriptional regulation and activation of BMP-2-Smad signaling by NF-kappaB in metastatic prostate cancer cells. Prostate 69: 168–180.

    Article  PubMed  CAS  Google Scholar 

  39. Eliseev, R.A., E.M. Schwarz, M.J. Zuscik, R.J. O'Keefe, H. Drissi, and R.N. Rosier. 2006. Smad7 mediates inhibition of Saos2 osteosarcoma cell differentiation by NFkappaB. Experimental Cell Research 312: 40–50.

    Article  PubMed  CAS  Google Scholar 

  40. Ren, X.Y., Q.R. Ruan, D.H. Zhu, M. Zhu, Z.L. Qu, and J. Lu. 2007. Tetramethylpyrazine inhibits angiotensin II-induced nuclear factor-kappaB activation and bone morphogenetic protein-2 downregulation in rat vascular smooth muscle cells. Sheng Li Xue Bao 59: 339–344.

    PubMed  CAS  Google Scholar 

  41. Zhang, R., J.R. Edwards, S.Y. Ko, S. Dong, H. Liu, B.O. Oyajobi, C. Papasian, H.W. Deng, and M. Zhao. 2011. Transcriptional regulation of BMP2 expression by the PTH-CREB signaling pathway in osteoblasts. PLoS One 6: e20780.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

The study was supported by the fund of Shanghai Jiao-Tong University School of Medicine for science and technology research (YZ1034). We thank Dr. C. Guo of Fudan University for technical assistance and his help in revising this manuscript.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Renji Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, People’s Republic of China

    Yongyi Wang, Jianggui Shan, Wengang Yang, Hui Zheng & Song Xue

Authors
  1. Yongyi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianggui Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wengang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Song Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Song Xue.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, Y., Shan, J., Yang, W. et al. High Mobility Group Box 1 (HMGB1) Mediates High-Glucose-Induced Calcification in Vascular Smooth Muscle Cells of Saphenous Veins. Inflammation 36, 1592–1604 (2013). https://doi.org/10.1007/s10753-013-9704-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-013-9704-1

KEY WORDS

Search

Navigation