Skip to main content

Advertisement

SpringerLink
Log in

Fetuin-B regulates vascular plaque rupture via TGF-β receptor-mediated Smad pathway in vascular smooth muscle cells

  • Molecular and cellular mechanisms of disease
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Fetuin-B is a serum protein linked to the regulation of physiological or pathophysiological events such as fertility, energy metabolism, and liver disease. Recently, fetuin-B has been reported to be involved in the modulation of the rupture of atherosclerotic plaques associated with acute myocardial infarction. However, the exact mechanism involved in the modulation of atherosclerotic plaque rupture event by fetuin-B is not fully elucidated yet. In the present study, we investigated whether fetuin-B could influence atherosclerotic plaque rupture through vascular smooth muscle cells (VSMCs). Immunoprecipitation assay using membrane proteins from VSMCs revealed that fetuin-B tightly bound to transforming growth factor-β receptor (TGF-βR). Fetuin-B treatment elevated TGF-βR signals (e.g., phosphorylation of Smad2 and Smad3) in VSMCs. Fetuin-B also stimulated nuclear translocation of phosphorylated Smads. Phosphorylation of Smad and its nuclear translocation by treatment with fetuin-B were inhibited in VSMCs by treatment with SB431542, a selective inhibitor of TGF-βR. Fetuin-B enhanced expression levels of plasminogen activator inhibitor-1 (PAI-1) and matrix metalloproteinase-2 (MMP-2) in VSMCs through its epigenetic modification including recruitments of both histone deacetylase 1 and RNA polymerase II. These epigenetic alterations in VSMCs were also inhibited by treatment with SB431542. In vivo administration of fetuin-B protein increased expression levels of PAI-1 and MMP-2 in the vascular plaque. However, these increases in expression were inhibited by the administration of SB43154. These results indicate that fetuin-B may modulate vascular plaque rupture by promoting expression of PAI-1 and MMP-2 in VSMCs via TGF-βR-mediated Smad pathway.

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

Similar content being viewed by others

References

  1. Afsar CU, Uzun H, Yurdakul S, Muderrisoglu C, Ergüney M, Demir B, Aslan A, Aral H, Ozyazgan S (2012) Association of serum fetuin-A levels with heart valve calcification and other biomarkers of inflammation among persons with acute coronary syndrome. Clin Invest Med 35:E206–E215

    Article  CAS  PubMed  Google Scholar 

  2. Basar N, Sen N, Kanat S, Ozlu MF, Ozcan F, Cay S, Erden G, Cagli KE, Yildirimkaya M, Maden O, Covic A, Kanbay M (2011) Lower fetuin-A predicts angiographic impaired reperfusion and mortality in ST-elevation myocardial infarction. Investig Med 59:816–822

    Article  Google Scholar 

  3. Braganza DM, Bennett MR (2001) New insights into atherosclerotic plaque rupture. Postgrad Med J 77:94–98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chen F, Eriksson P, Hansson GK, Herzfeld I, Klein M, Hansson LO, Valen G (2005) Expression of matrix metalloproteinase 9 and its regulators in the unstable coronary atherosclerotic plaque. Int J Mol Med 15:57–65

    CAS  PubMed  Google Scholar 

  5. Chen YG, Meng AM (2004) Negative regulation of TGF-β signaling in development. Cell Res 14:441–449

    Article  CAS  PubMed  Google Scholar 

  6. Demetriou M, Binkert C, Sukhu B, Tenenbaum HC, Dennis JW (1996) Fetuin/alpha2-HS glycoprotein is a transforming growth factor-β type II receptor mimic and cytokine antagonist. J Biol Chem 271:12755–12761

    Article  CAS  PubMed  Google Scholar 

  7. Denecke B, Gräber S, Schäfer C, Heiss A, Wöltje M, Jahnen-Dechent W (2003) Tissue distribution and activity testing suggest a similar but not identical function of fetuin-B and fetuin-A. Biochem J 376:135–145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dhawan S, Dirice E, Kulkarni RN, Bhushan A (2016) Inhibition of TGF-β signaling promotes human pancreatic β-cell replication. Diabetes 65:1208–1218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Falk E, Shah PK, Fuster V (1995) Coronary plaque disruption. Circulation 92:657–671

    Article  CAS  PubMed  Google Scholar 

  10. Fishbein MC (2010) The vulnerable and unstable atherosclerotic plaque. Cardiovasc Pathol 19:6–11

    Article  PubMed  Google Scholar 

  11. Galis ZS, Sukhova GK, Lark MW, Libby P (1994) Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 94:2493–2503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Grønholdt ML, Dalager-Pedersen S, Falk E (1998) Coronary atherosclerosis: determinants of plaque rupture. Eur Heart J 19(Suppl C):C24–C29

    PubMed  Google Scholar 

  13. Heldin CH, Miyazono K, ten Dijke P (1997) TGF-β signaling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471

    Article  CAS  PubMed  Google Scholar 

  14. Hojo Y, Ikeda U, Ta K, Mizuno O, Fujikawa H, Shimada K (2002) Matrix metalloproteinase expression in the coronary circulation induced by coronary angioplasty. Atherosclerosis 161:185–192

    Article  CAS  PubMed  Google Scholar 

  15. Hsu SJ, Nagase H, Balmain A (2004) Identification of Fetuin-B as a member of a cystatin-like gene family on mouse chromosome 16 with tumor suppressor activity. Genome 47:931–946

    Article  CAS  PubMed  Google Scholar 

  16. Jahnen-Dechent W, Schinke T, Trindl A, Müller-Esterl W, Sablitzky F, Kaiser S, Blessing M (1997) Cloning and targeted deletion of the mouse fetuin gene. J Biol Chem 272:31496–31503

    Article  CAS  PubMed  Google Scholar 

  17. Jung SH, Won KJ, Lee KP, Kim HJ, Seo EH, Lee HM, Park ES, Lee SH, Kim B (2015) The serum protein fetuin-B is involved in the development of acute myocardial infarction. Clin Sci (Lond) 129:27–38

    Article  CAS  Google Scholar 

  18. Lee C, Bongcam-Rudloff E, Sollner C, Jahnen-Dechent W, Claesson-Welsh L (2009) Type 3 cystatins; fetuins, kininogen and histidine-rich glycoprotein. Front Biosci (Landmark Ed) 14:2911–2922

    Article  CAS  Google Scholar 

  19. Lee DY, Kim HS, Won KJ, Lee KP, Jung SH, Park ES, Choi WS, Lee HM, Kim B (2015) DJ-1 regulates the expression of renal (pro)renin receptor via reactive oxygen species-mediated epigenetic modification. Biochim Biophys Acta 1850:426–434

    Article  CAS  PubMed  Google Scholar 

  20. Lee KP, Baek S, Jung SH, Cui L, Lee D, Lee DY, Choi WS, Chung HW, Lee BH, Kim B, Won KJ (2018) DJ-1 is involved in epigenetic control of sphingosine-1-phosphate receptor expression in vascular neointima formation. Pflugers Arch 470:1103–1113

    Article  CAS  PubMed  Google Scholar 

  21. Li Z, Li L, Zielke HR, Cheng L, Xiao R, Crow MT, Stetler-Stevenson WG, Froehlich J, Lakatta EG (1996) Increased expression of 72-kd type IV collagenase (MMP-2) in human aortic atherosclerotic lesions. Am J Pathol 148:121–128

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lijnen HR (2001) Elements of the fibrinolytic system. Ann N Y Acad Sci 936:226–236

    Article  CAS  PubMed  Google Scholar 

  23. Lim P, Moutereau S, Simon T, Gallet R, Probst V, Ferrieres J, Gueret P, Danchin N (2013) Usefulness of fetuin-A and C-reactive protein concentrations for prediction of outcome in acute coronary syndromes (from the French Registry of Acute ST-Elevation Non-ST-Elevation Myocardial Infarction [FAST-MI]). Am J Cardiol 111:31–37

    Article  CAS  PubMed  Google Scholar 

  24. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  25. Lu P, Takai K, Weaver VM, Werb Z (2011) Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 3:a005058

    Article  PubMed  PubMed Central  Google Scholar 

  26. Meex RC, Hoy AJ, Morris A, Brown RD, Lo JC, Burke M, Goode RJ, Kingwell BA, Kraakman MJ, Febbraio MA, Greve JW, Rensen SS, Molloy MP, Lancaster GI, Bruce CR, Watt MJ (2015) Fetuin B is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism. Cell Metab 22:1078–1089

    Article  CAS  PubMed  Google Scholar 

  27. Murakami T, Walczak R, Caron S, Duhem C, Vidal V, Darteil R, Staels B (2007) The farnesoid X receptor induces fetuin-B gene expression in human hepatocytes. Biochem J 407:461–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nadkarni SK, Bouma BE, de Boer J, Tearney GJ (2009) Evaluation of collagen in atherosclerotic plaques: the use of two coherent laser-based imaging methods. Lasers Med Sci 24:439–445

    Article  PubMed  Google Scholar 

  29. Newby AC, Zaltsman AB (1999) Fibrous cap formation or destruction--the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. Cardiovasc Res 41:345–360

    Article  CAS  PubMed  Google Scholar 

  30. Pandolfi A, Cetrullo D, Polishuck R, Alberta MM, Calafiore A, Pellegrini G, Vitacolonna E, Capani F, Consoli A (2001) Plasminogen activator inhibitor type 1 is increased in the arterial wall of type II diabetic subjects. Arterioscler Thromb Vasc Biol 21:1378–1382

    Article  CAS  PubMed  Google Scholar 

  31. Ploplis VA (2011) Effects of altered plasminogen activator inhibitor-1 expression on cardiovascular disease. Curr. Drug Targets 12:1782–1789

    Article  CAS  Google Scholar 

  32. Santibañez JF, Quintanilla M, Bernabeu C (2011) TGF-β/TGF-β receptor system and its role in physiological and pathological conditions. Clin Sci (Lond) 121:233–251

    Article  CAS  Google Scholar 

  33. Shah PK (2002) Pathophysiology of coronary thrombosis: role of plaque rupture and plaque erosion. Prog Cardiovasc Dis 44:357–368

    Article  PubMed  Google Scholar 

  34. Shah PK, Galis ZS (2001) Matrix metalloproteinase hypothesis of plaque rupture: players keep piling up but questions remain. Circulation 104:1878–1880

    Article  CAS  PubMed  Google Scholar 

  35. Shi Y, Massagué J (2003) Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113:685–700

    Article  CAS  PubMed  Google Scholar 

  36. Suwanabol PA, Seedial SM, Zhang F, Shi X, Si Y, Liu B, Kent KC (2012) TGF-β and Smad3 modulate PI3K/Akt signaling pathway in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 302:H2211–H2219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Swedenborg J, Eriksson P (2006) The intraluminal thrombus as a source of proteolytic activity. Ann N Y Acad Sci 1085:133–138

    Article  CAS  PubMed  Google Scholar 

  38. Volcik KA, Campbell S, Chambless LE, Coresh J, Folsom AR, Mosley TH, Ni H, Wagenknecht LE, Wasserman BA, Boerwinkle E (2010) MMP2 genetic variation is associated with measures of fibrous cap thickness: the atherosclerosis risk in communities carotid MRI study. Atherosclerosis 210:188–193

    Article  CAS  PubMed  Google Scholar 

  39. Wang J, Uryga AK, Reinhold J, Figg N, Baker L, Finigan A, Gray K, Kumar S, Clarke M, Bennett M (2015) Vascular smooth muscle cell senescence promotes atherosclerosis and features of plaque vulnerability. Circulation 132:1909–1919

    Article  CAS  PubMed  Google Scholar 

  40. Weikert C, Stefan N, Schulze MB, Pischon T, Berger K, Joost HG, Häring HU, Boeing H, Fritsche A (2008) Plasma fetuin-a levels and the risk of myocardial infarction and ischemic stroke. Circulation 118:2555–2562

    Article  CAS  PubMed  Google Scholar 

  41. Wu ML, Chen CH, Lin YT, Jheng YJ, Ho YC, Yang LT, Chen L, Layne MD, Yet SF (2014) Divergent signaling pathways cooperatively regulate TGFβ induction of cysteine-rich protein 2 in vascular smooth muscle cells. Cell Commun Signal 12:22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Korean government (NRF-2016R1D1A1B03934204; 2017R1D1A1B03035674). It was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C1540).

Author information

Authors and Affiliations

  1. Department of Physiology, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, South Korea

    Seung Hyo Jung, Donghyen Lee, Hengzhe Jin, Kyung-Jin Lee, Su Jung Kim, Yunkyoung Ryu, Wahn Soo Choi, Bokyung Kim & Kyung-Jong Won

  2. Department of Cosmetic Science, College of Life and Health Science, Hoseo University, Asan, 31499, South Korea

    Hwan Myung Lee

  3. Department of Life Sciences, College of Science and Technology, Woosuk University, Jincheon, 27841, South Korea

    Hyun Myung Ko

Authors
  1. Seung Hyo Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donghyen Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hengzhe Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hwan Myung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyun Myung Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kyung-Jin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Su Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yunkyoung Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wahn Soo Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bokyung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kyung-Jong Won
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.H.J. and K.-J.W. conceived and designed the study. S.H.J., D.L., H.J., K.J.L., S.J.K., and Y.R. performed experiments and data acquisition. S.H.J., D.L., and H.J. prepared the figures. S.H.J., D.L., H.M.L., H.M.K., W.S.C., and K.-J.W. analyzed and interpreted the data. S.H.L., B.K., and K.-J.W. drafted and revised manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Kyung-Jong Won.

Ethics declarations

All animal procedures in this study were in strict adherence to the Guide for the Care and Use of Laboratory Animals as adopted by the U.S. National Institutes of Health (NIH publication No. 85-23, revised 1996) and were approved by the Animal Subjects Committee and by the Institutional Guidelines of Konkuk University, South Korea.

Conflict of interest

The authors declare that there are no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 182 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jung, S.H., Lee, D., Jin, H. et al. Fetuin-B regulates vascular plaque rupture via TGF-β receptor-mediated Smad pathway in vascular smooth muscle cells. Pflugers Arch - Eur J Physiol 472, 571–581 (2020). https://doi.org/10.1007/s00424-020-02385-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-020-02385-2

Keywords

Search

Navigation