Skip to main content

Advertisement

SpringerLink
Log in

Possible role of fibroblast growth factor 21 on atherosclerosis via amelioration of endoplasmic reticulum stress-mediated apoptosis in apoE−/− mice

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Fibroblast growth factor 21 (FGF-21) is an endocrine factor that can be secreted into circulation by the liver. FGF-21 takes part in metabolic actions and is thought to be a promising candidate for the treatment of diabetes. However, the role of FGF-21 in atherosclerosis is unknown. In this study, apoE−/− mice were fed an atherogenic diet for 4 weeks with and without subcutaneous injections of FGF-21. ApoE−/− mice fed an atherogenic diet showed hyperlipidemia, a large plaque area in aortas and increased vessel wall thickness. Plasma FGF-21 content and protein level of FGF receptor 1 (FGFR1) in aortas was greater in apoE−/− than C57BL/6J mice. Exogenous FGF-21 treatment significantly ameliorated dyslipidemia in apoE−/− mice. FGF-21–treated apoE−/− mice showed reduced number of aortic plaques and plaque area as well as reduced number of TUNEL-positive cells. Protein levels of the endoplasmic reticulum stress markers glucose-regulated protein 94, caspase-12 and C/EBP homologous protein were reduced by 34.5, 31.4 and 26.5 %, respectively, in apoE−/− mice. Endogenous expression of FGF-21 and its receptor FGFR1 were upregulated in apoE−/− mice, and exogenous administration of FGF-21 ameliorated the atherogenic-induced dyslipidemia and vascular atherosclerotic lesions. FGF-21 protecting against atherosclerosis might be in part by its inhibitory effects on endoplasmic reticulum stress-mediated apoptosis.

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. Lusis AJ (2000) Atherosclerosis. Nature 407:233–241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Pan CS, Zhang J, Yu F, Teng X, Cao CQ, Wu W, Tang CS, Qi YF (2010) Adrenomedullin ameliorates the development of atherosclerosis in apoE-/- mice. Peptides 31:1150–1158

    Article  CAS  PubMed  Google Scholar 

  3. Napoli C, de Nigris F, Williams-Ignarro S, Pignalosa O, Sica V, Ignarro LJ (2006) Nitric oxide and atherosclerosis: an update. Nitric Oxide 15:265–279

    Article  CAS  PubMed  Google Scholar 

  4. Ichiki T, Izumi R, Cataliotti A, Larsen AM, Sandberg SM, Burnett JC Jr (2013) Endothelial permeability in vitro and in vivo: protective actions of anp and omapatrilat in experimental atherosclerosis. Peptides 48:21–26

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Li MW, Mian MO, Barhoumi T, Rehman A, Mann K, Paradis P, Schiffrin EL (2013) Endothelin-1 overexpression exacerbates atherosclerosis and induces aortic aneurysms in apolipoprotein e knockout mice. Arterioscler Thromb Vasc Biol 33:2306–2315

    Article  CAS  PubMed  Google Scholar 

  6. Weiss D, Kools JJ, Taylor WR (2001) Angiotensin ii-induced hypertension accelerates the development of atherosclerosis in apoe-deficient mice. Circulation 103:448–454

    Article  CAS  PubMed  Google Scholar 

  7. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB (2005) Fgf-21 as a novel metabolic regulator. J Clin Invest 115:1627–1635

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Iglesias P, Selgas R, Romero S, Diez JJ (2012) Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21. Eur J Endocrinol 167:301–309

    Article  CAS  PubMed  Google Scholar 

  9. Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, Goetz R, Mohammadi M, Kuro-o M, Mangelsdorf DJ, Kliewer SA (2010) Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 24:2050–2064

    Article  PubMed Central  PubMed  Google Scholar 

  10. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A (2008) Serum fgf21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57:1246–1253

    Article  CAS  PubMed  Google Scholar 

  11. Crasto C, Semba RD, Sun K, Ferrucci L (2012) Serum fibroblast growth factor 21 is associated with renal function and chronic kidney disease in community-dwelling adults. J Am Geriatr Soc 60:792–793

    Article  PubMed Central  PubMed  Google Scholar 

  12. Semba RD, Crasto C, Strait J, Sun K, Schaumberg DA, Ferrucci L (2013) Elevated serum fibroblast growth factor 21 is associated with hypertension in community-dwelling adults. J Hum Hypertens 27:397–399

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Lin Z, Wu Z, Yin X, Liu Y, Yan X, Lin S, Xiao J, Wang X, Feng W, Li X (2010) Serum levels of fgf-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile. PLoS One 5:e15534

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Liu SQ, Kharitonenkov Alexei, Zhang LQ, Wu YH (2012) Myocardial ischemia-induced hepatic fibroblast growth factor 21 for cardioprotection. Circulation 126:A12573

    Google Scholar 

  15. Lu Y, Liu JH, Zhang LK, Du J, Zeng XJ, Hao G, Huang J, Zhao DH, Wang GZ, Zhang YC (2010) Fibroblast growth factor 21 as a possible endogenous factor inhibits apoptosis in cardiac endothelial cells. Chin Med J (Engl) 123:3417–3421

    CAS  Google Scholar 

  16. Minamino T, Kitakaze M (2010) Er stress in cardiovascular disease. J Mol Cell Cardiol 48:1105–1110

    Article  CAS  PubMed  Google Scholar 

  17. Hotamisligil GS (2010) Endoplasmic reticulum stress and atherosclerosis. Nat Med 16:396–399

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Gorman AM, Healy SJ, Jager R, Samali A (2012) Stress management at the er: Regulators of er stress-induced apoptosis. Pharmacol Ther 134:306–316

    Article  CAS  PubMed  Google Scholar 

  19. Oyadomari S, Araki E, Mori M (2002) Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis 7:335–345

    Article  CAS  PubMed  Google Scholar 

  20. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403:98–103

    Article  CAS  PubMed  Google Scholar 

  21. Tabas I (2010) The role of endoplasmic reticulum stress in the progression of atherosclerosis. Circ Res 107:839–850

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Schrijvers DM, De Meyer GR, Herman AG, Martinet W (2007) Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaque progression and stability. Cardiovasc Res 73:470–480

    Article  CAS  PubMed  Google Scholar 

  23. Seimon T, Tabas I (2009) Mechanisms and consequences of macrophage apoptosis in atherosclerosis. J Lipid Res 50(Suppl):S382–S387

    PubMed Central  PubMed  Google Scholar 

  24. Paigen B, Morrow A, Holmes PA, Mitchell D, Williams RA (1987) Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 68:231–240

    Article  CAS  PubMed  Google Scholar 

  25. Lee SA, Jeong E, Kim EH, Shin MS, Hwang JY, Koh EH, Lee WJ, Park JY, Kim MS (2012) Various oscillation patterns of serum fibroblast growth factor 21 concentrations in healthy volunteers. Diabetes Metab J 36:29–36

    Article  PubMed Central  PubMed  Google Scholar 

  26. Rask-Madsen C, Li Q, Freund B, Feather D, Abramov R, Wu IH, Chen K, Yamamoto-Hiraoka J, Goldenbogen J, Sotiropoulos KB, Clermont A, Geraldes P, Dall’Osso C, Wagers AJ, Huang PL, Rekhter M, Scalia R, Kahn CR, King GL (2010) Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein e null mice. Cell Metab 11:379–389

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Lee MS, Choi SE, Ha ES, An SY, Kim TH, Han SJ, Kim HJ, Kim DJ, Kang Y, Lee KW (2012) Fibroblast growth factor-21 protects human skeletal muscle myotubes from palmitate-induced insulin resistance by inhibiting stress kinase and nf-kappab. Metabolism 61:1142–1151

    Article  CAS  PubMed  Google Scholar 

  28. Feingold KR, Grunfeld C, Heuer JG, Gupta A, Cramer M, Zhang T, Shigenaga JK, Patzek SM, Chan ZW, Moser A, Bina H, Kharitonenkov A (2012) FGF21 is increased by inflammatory stimuli and protects leptin-deficient ob/ob mice from the toxicity of sepsis. Endocrinology 153:2689–2700

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A (2008) Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149:6018–6027

    Article  CAS  PubMed  Google Scholar 

  30. Lundasen T, Hunt MC, Nilsson LM, Sanyal S, Angelin B, Alexson SE, Rudling M (2007) PPARalpha is a key regulator of hepatic FGF21. Biochem Biophys Res Commun 360:437–440

    Article  CAS  PubMed  Google Scholar 

  31. Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, Kliewer SA (2012) Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones. Cell 148:556–567

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Li AC, Binder CJ, Gutierrez A, Brown KK, Plotkin CR, Pattison JW, Valledor AF, Davis RA, Willson TM, Witztum JL, Palinski W, Glass CK (2004) Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest 114:1564–1576

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Christoph M, Herold J, Berg-Holldack A, Rauwolf T, Ziemssen T, Schmeisser A, Weinert S, Ebner B, Said S, Strasser RH, Braun-Dullaeus RC (2014) Effects of the PPARgamma agonist pioglitazone on coronary atherosclerotic plaque composition and plaque progression in non-diabetic patients: A double-center, randomized controlled vh-ivus pilot-trial. Heart Vessels. doi:10.1007/s00380-014-0480-0

    PubMed  Google Scholar 

  34. Xu J, Lloyd DJ, Hale C, Stanislaus S, Chen M, Sivits G, Vonderfecht S, Hecht R, Li YS, Lindberg RA, Chen JL, Jung DY, Zhang Z, Ko HJ, Kim JK, Veniant MM (2009) Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice. Diabetes 58:250–259

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874

    Article  CAS  PubMed  Google Scholar 

  36. Hong SH, Jang HH, Lee SR, Lee KH, Woo JS, Kim JB, Kim WS, Min BI, Cho KH, Kim KS, Cheng X, Kim W (2014) Impact of lysophosphatidylcholine on survival and function of UEA-1 + acLDL + endothelial progenitor cells in patients with coronary artery disease. Heart Vessels. doi:10.1007/s00380-014-0473-z

    Google Scholar 

  37. Durand E, Scoazec A, Lafont A, Boddaert J, Al Hajzen A, Addad F, Mirshahi M, Desnos M, Tedgui A, Mallat Z (2004) In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation: A clue to the understanding of the mechanisms of thrombotic plaque erosion. Circulation 109:2503–2506

    Article  CAS  PubMed  Google Scholar 

  38. Staiger K, Staiger H, Weigert C, Haas C, Haring HU, Kellerer M (2006) Saturated, but not unsaturated, fatty acids induce apoptosis of human coronary artery endothelial cells via nuclear factor-kappab activation. Diabetes 55:3121–3126

    Article  CAS  PubMed  Google Scholar 

  39. Tabas I (2005) Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: The importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol 25:2255–2264

    Article  CAS  PubMed  Google Scholar 

  40. Thorp E, Li G, Seimon TA, Kuriakose G, Ron D, Tabas I (2009) Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of apoe-/- and ldlr-/- mice lacking chop. Cell Metab 9:474–481

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Myoishi M, Hao H, Minamino T, Watanabe K, Nishihira K, Hatakeyama K, Asada Y, Okada K, Ishibashi-Ueda H, Gabbiani G, Bochaton-Piallat ML, Mochizuki N, Kitakaze M (2007) Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation 116:1226–1233

    Article  PubMed  Google Scholar 

  42. Seimon T, Tabas I (2009) Mechanisms and consequences of macrophage apoptosis in atherosclerosis. J Lipid Res 50:S382–S387

    Article  PubMed Central  PubMed  Google Scholar 

  43. Zhou AX, Tabas I (2013) The UPR in atherosclerosis. Semin Immunopathol 35:321–332

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Jiang X, Zhang C, Xin Y, Huang Z, Tan Y, Huang Y, Wang Y, Feng W, Li X, Li W, Qu Y, Cai L (2013) Protective effect of FGF21 on type 1 diabetes-induced testicular apoptotic cell death probably via both mitochondrial- and endoplasmic reticulum stress-dependent pathways in the mouse model. Toxicol Lett 219:65–76

    Article  CAS  PubMed  Google Scholar 

  45. Hu P, Han Z, Couvillon AD, Exton JH (2004) Critical role of endogenous Akt/IAPS and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death. J Biol Chem 279:49420–49429

    Article  CAS  PubMed  Google Scholar 

  46. Zulli A, Lau E, Wijaya BP, Jin X, Sutarga K, Schwartz GD, Learmont J, Wookey PJ, Zinellu A, Carru C, Hare DL (2009) High dietary taurine reduces apoptosis and atherosclerosis in the left main coronary artery: Association with reduced ccaat/enhancer binding protein homologous protein and total plasma homocysteine but not lipidemia. Hypertension 53:1017–1022

    Article  CAS  PubMed  Google Scholar 

  47. Eletto D, Dersh D, Argon Y (2010) Grp94 in er quality control and stress responses. Semin Cell Dev Biol 21:479–485

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Zhao Q, Hu X, Shao L, Wu G, Du J, Xia J (2013) Lipoxina attenuates myocardial ischemia reperfusion injury via a mechanism related to downregulation of grp-78 and caspase-12 in rats. Heart Vessels. doi:10.1007/s00380-013-0418-y

    PubMed Central  Google Scholar 

  49. Stoneman VE, Bennett MR (2004) Role of apoptosis in atherosclerosis and its therapeutic implications. Clin Sci (Lond) 107:343–354

    Article  CAS  Google Scholar 

  50. Feng B, Yao PM, Li Y, Devlin CM, Zhang D, Harding HP, Sweeney M, Rong JX, Kuriakose G, Fisher EA, Marks AR, Ron D, Tabas I (2003) The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol 5:781–792

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 81070227 to Jing-Hua Liu).

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Cardiology, Fuwai Hospital and National Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, China

    Xi Wu

  2. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, 2 Anzhen Road, Chaoyang District, Beijing, 100029, China

    Xi Wu, Shao-Ping Wang, Shu-Juan Cheng, Ming Zhang, Qian Fan, Yuan Lv, Hui Zhu, Man-Kun Xin, Yun Lv & Jing-Hua Liu

  3. Laboratory of Cardiovascular Bioactive Molecule, School of Basic Medical Sciences, Peking University, Beijing, 100191, China

    Yong-Fen Qi, Jin-Rui Chang, Wei-Wei Lu & Jin-Sheng Zhang

  4. Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, 100191, China

    Yong-Fen Qi

Authors
  1. Xi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yong-Fen Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin-Rui Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei-Wei Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jin-Sheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shao-Ping Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shu-Juan Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qian Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yuan Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hui Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Man-Kun Xin
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yun Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jing-Hua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jing-Hua Liu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, X., Qi, YF., Chang, JR. et al. Possible role of fibroblast growth factor 21 on atherosclerosis via amelioration of endoplasmic reticulum stress-mediated apoptosis in apoE−/− mice. Heart Vessels 30, 657–668 (2015). https://doi.org/10.1007/s00380-014-0557-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-014-0557-9

Keywords

Search

Navigation