Skip to main content

Advertisement

Log in

Hepatocyte growth factor protects endothelial progenitor cell from damage of low-density lipoprotein cholesterol via the PI3K/Akt signaling pathway

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Risk factors for coronary heart disease including low-density lipoprotein (LDL) cholesterol can reduce the number and activity of endothelial progenitor cells (EPCs), thereby hindering their usefulness for treating cardiovascular disease in transplants. The aim of this study was to investigate whether hepatocyte growth factor (HGF) can protect EPCs from the inhibition caused by LDL cholesterol. EPCs derived from mouse bone marrow were isolated and cultured in medium supplemented with different concentrations of LDL cholesterol. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, modified Boyden chambers and flow cytometry were used to evaluate EPC proliferation, migration and apoptosis. The role of Akt in this process was also evaluated through observing the expressions of total Akt and Akt phosphorylation, and pharmacological analysis. Our results indicate that LDL cholesterol inhibits the proliferation and migration of EPCs, and induces their apoptosis. However, HGF improves the activity of EPCs inhibited by LDL cholesterol, and it simultaneously decreases EPC apoptosis induced by LDL cholesterol. Blockade of phosphoinositide-3 kinase (PI3K) by Ly294002 attenuates the effect of HGF. Furthermore, our experiments suggest that HGF increases the level of phosphorylated Akt in EPCs rather than Akt. However, PI3K inhibitor reduces the increase of phosphorylated Akt level induced by HGF. These findings suggest HGF promotes endothelial progenitor cells migration, proliferation and survival impaired by low-density lipoprotein cholesterol via the PI3K/Akt signaling pathway.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Shoji M, Sata M, Fukuda D et al (2004) Temporal and spatial characterization of cellular constituents during neointimal hyperplasia after vascular injury: potential contribution of bone-marrow-derived progenitors to arterial remodeling. Cardiovasc Pathol 13:306–312

    Article  PubMed  Google Scholar 

  2. Condon ET, Wang JH, Redmond HP (2004) Surgical injury induces the mobilization of endothelial progenitor cells. Surgery 135:657–661

    Article  CAS  PubMed  Google Scholar 

  3. Campagnolo L, Leahy A, Chitnis S et al (2005) EGFL7 is a chemoattractant for endothelial cells and is up-regulated in angiogenesis and arterial injury. Am J Pathol 167:275–284

    CAS  PubMed  Google Scholar 

  4. Del Papa N, Quirici N, Soligo D et al (2006) Bone marrow endothelial progenitors are defective in systemic sclerosis. Arthritis Rheum 54:2605–2615

    Article  CAS  PubMed  Google Scholar 

  5. Urbich C, Dimmeler S (2004) Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 95:343–353

    Article  CAS  PubMed  Google Scholar 

  6. Hunting CB, Noort WA, Zwaginga JJ (2005) Circulating endothelial (progenitor) cells reflect the state of the endothelium: vascular injury, repair and neovascularization. Vox Sang 88:1–9

    Article  CAS  PubMed  Google Scholar 

  7. Werner N, Junk S, Laufs U et al (2003) Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury. Circ Res 93:e17–e24

    Article  CAS  PubMed  Google Scholar 

  8. Kocher AA, Schuster MD, Szabolcs MJ et al (2001) Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7:430–436

    Article  CAS  PubMed  Google Scholar 

  9. Lyden D, Hattori K, Dias S et al (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7:1194–1201

    Article  CAS  PubMed  Google Scholar 

  10. Gill M, Dias S, Hattori K et al (2001) Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ Res 88:167–174

    CAS  PubMed  Google Scholar 

  11. Shake JG, Gruber PJ, Baumgartner WA et al (2002) Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg 73:1919–1925 (discussion 1926)

    Article  PubMed  Google Scholar 

  12. Ueno T, Sata M (2002) Forefront of therapy for hepatic fibrosis. Nippon Shokakibyo Gakkai Zasshi 99:365–378

    CAS  PubMed  Google Scholar 

  13. Werner N, Nickenig G (2006) Influence of cardiovascular risk factors on endothelial progenitor cells: limitations for therapy? Arterioscler Thromb Vasc Biol 26:257–266

    Article  CAS  PubMed  Google Scholar 

  14. Hill JM, Zalos G, Halcox JP et al (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348:593–600

    Article  PubMed  Google Scholar 

  15. Werner N, Kosiol S, Schiegl T et al (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353:999–1007

    Article  CAS  PubMed  Google Scholar 

  16. Farahani P, Levine M (2009) Goal attainment for multiple cardiovascular risk factors in community-based clinical practice (a Canadian experience). J Eval Clin Pract 15:212–216

    Article  PubMed  Google Scholar 

  17. Ma FX, Zhou B, Chen Z et al (2006) Oxidized low density lipoprotein impairs endothelial progenitor cells by regulation of endothelial nitric oxide synthase. J Lipid Res 47:1227–1237

    Article  CAS  PubMed  Google Scholar 

  18. Cheng J, Cui R, Chen CH et al (2007) Oxidized low-density lipoprotein stimulates p53-dependent activation of proapoptotic Bax leading to apoptosis of differentiated endothelial progenitor cells. Endocrinology 148:2085–2094

    Article  CAS  PubMed  Google Scholar 

  19. Ishizawa K, Kubo H, Yamada M et al (2004) Hepatocyte growth factor induces angiogenesis in injured lungs through mobilizing endothelial progenitor cells. Biochem Biophys Res Commun 324:276–280

    Article  CAS  PubMed  Google Scholar 

  20. Trusolino L, Comoglio PM (2002) Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2:289–300

    Article  CAS  PubMed  Google Scholar 

  21. Birchmeier C, Birchmeier W, Gherardi E et al (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925

    Article  CAS  PubMed  Google Scholar 

  22. Iwakura A, Luedemann C, Shastry S et al (2003) Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury. Circulation 108:3115–3121

    Article  CAS  PubMed  Google Scholar 

  23. Vasa M, Fichtlscherer S, Aicher A et al (2001) Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89:E1–E7

    Article  CAS  PubMed  Google Scholar 

  24. Cines DB, Pollak ES, Buck CA et al (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527–3561

    CAS  PubMed  Google Scholar 

  25. Kong D, Melo LG, Mangi AA et al (2004) Enhanced inhibition of neointimal hyperplasia by genetically engineered endothelial progenitor cells. Circulation 109:1769–1775

    Article  CAS  PubMed  Google Scholar 

  26. Blindt R, Vogt F, Astafieva I et al (2006) A novel drug-eluting stent coated with an integrin-binding cyclic Arg-Gly-Asp peptide inhibits neointimal hyperplasia by recruiting endothelial progenitor cells. J Am Coll Cardiol 47:1786–1795

    Article  CAS  PubMed  Google Scholar 

  27. Roy-Chaudhury P (2005) Endothelial progenitor cells, neointimal hyperplasia, and hemodialysis vascular access dysfunction: novel therapies for a recalcitrant clinical problem. Circulation 112:3–5

    Article  PubMed  Google Scholar 

  28. Asahara T, Murohara T, Sullivan A et al (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967

    Article  CAS  PubMed  Google Scholar 

  29. Kawamoto A, Asahara T (2007) Role of progenitor endothelial cells in cardiovascular disease and upcoming therapies. Catheter Cardiovasc Interv 70:477–484

    Article  PubMed  Google Scholar 

  30. Xiao Q, Kiechl S, Patel S et al (2007) Endothelial progenitor cells, cardiovascular risk factors, cytokine levels and atherosclerosis—results from a large population-based study. PLoS ONE 2:e975

    Article  PubMed  Google Scholar 

  31. Balbarini A, Barsotti MC, Di Stefano R et al (2007) Circulating endothelial progenitor cells characterization, function and relationship with cardiovascular risk factors. Curr Pharm Des 13:1699–1713

    Article  CAS  PubMed  Google Scholar 

  32. Cai L, Johnstone BH, Cook TG et al (2007) Suppression of hepatocyte growth factor production impairs the ability of adipose-derived stem cells to promote ischemic tissue revascularization. Stem Cells 25:3234–3243

    Article  CAS  PubMed  Google Scholar 

  33. Zhou YJ, Wang JH, Zhang J (2006) Hepatocyte growth factor protects human endothelial cells against advanced glycation end products-induced apoptosis. Biochem Biophys Res Commun 344:658–666

    Article  CAS  PubMed  Google Scholar 

  34. Ishizawa K, Kubo H, Yamada M et al (2004) Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysema. FEBS Lett 556:249–252

    Article  CAS  PubMed  Google Scholar 

  35. Lee YH, Suzuki YJ, Griffin AJ et al (2008) Hepatocyte growth factor regulates cyclooxygenase-2 expression via beta-catenin, Akt, and p42/p44 MAPK in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 294:L778–L786

    Article  CAS  PubMed  Google Scholar 

  36. Kimura M, Okamoto H, Ogihara M (2007) Activation of mitogen-activated protein kinase by hepatocyte growth factor is stimulated by both alpha1- and beta2-adrenergic agonists in primary cultures of adult rat hepatocytes. J Pharmacol Sci 103:398–407

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study is supported by grants from the National Natural Science Foundation of China (No. 30570765 and No. 30700889) and the Natural Science Foundation of Chongqing, China (No. CSTC, 2005bb5304).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lan Hunag.

Additional information

XueJun Yu and MingBao Song contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yu, X., Song, M., Chen, J. et al. Hepatocyte growth factor protects endothelial progenitor cell from damage of low-density lipoprotein cholesterol via the PI3K/Akt signaling pathway. Mol Biol Rep 37, 2423–2429 (2010). https://doi.org/10.1007/s11033-009-9753-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-009-9753-6

Keywords

Navigation