Skip to main content
Log in

Octacosanol Enhances the Proliferation and Migration of Human Umbilical Vein Endothelial Cells via Activation of the PI3K/Akt and MAPK/Erk Pathways

  • Original Article
  • Published:
Lipids

Abstract

Atherosclerosis is characterized by endothelial dysfunction, lipid deposition, fibro-proliferative reactions and inflammation. Octacosanol is a high-molecular-weight primary aliphatic alcohol. As the main component of a cholesterol-lowering drug, octacosanol could inhibit lipids accumulation and cholesterol metabolism. To explore the indication of octacosanol on endothelial protection, we evaluated its effects on the proliferation and migration of human umbilical vein endothelial cells (HUVEC). Cell viability assay using methyl thiazolyl tetrazolium and 5-ethynyl-2′-deoxyuridine revealed that 3.125 μg/ml octacosanol promoted the proliferation of HUVEC. A cell migration assay indicated that 0.781 and 3.125 μg/ml octacosanol increased the migration of HUVEC. Moreover, the phosphorylation levels of Akt and Erk1/2 were significantly elevated under exposure to octacosanol. Blocking the activation of Akt and Erk with their potent inhibitors LY294002 and PD98059, respectively, markedly attenuated the octacosanol-induced proliferation and migration of HUVEC. These findings demonstrated for the first time that octacosanol enhanced the proliferation and migration of HUVEC and mediated these effects through activation of the PI3K/Akt and MAPK/Erk1/2 signaling pathways.

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

Access this article

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
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

HUVEC:

Human umbilical vein endothelial cells

PI3K/Akt:

Phosphatidylinositol-3-kinase/Akt

MAPK/Erk1/2:

Mitogen-activated protein kinases/Erk1/2

HMGR:

Hydroxymethylglutaryl-coenzyme A reductase

VEGF:

Vascular endothelial growth factor

CHD:

Coronary heart disease

MTT :

3-[4, 5-Dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide

EdU:

5-Ethynyl-2′-deoxyuridine

FBS:

Fetal bovine serum

References

  1. Kato S, Karino K, Hasegawa S et al (1995) Octacosanol affects lipid metabolism in rats fed on a high-fat diet. Br J Nutr 73(3):433–441

    Article  CAS  PubMed  Google Scholar 

  2. Keller S, Gimmler F, Jahreis G (2008) Octacosanol administration to humans decreases neutral sterol and bile acid concentration in feces. Lipids 43(2):109–115

    Article  CAS  PubMed  Google Scholar 

  3. Gouni-Berthold I, Berthold HK (2002) Policosanol: clinical pharmacology and therapeutic significance of a new lipid-lowering agent. Am Heart J 143(2):356–365

    Article  CAS  PubMed  Google Scholar 

  4. Oliaro-Bosso S, Calcio GE, Mantegna S et al (2009) Regulation of HMGCoA reductase activity by policosanol and octacosadienol, a new synthetic analogue of octacosanol. Lipids 44:907–916

    Article  CAS  PubMed  Google Scholar 

  5. Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362(6423):801–809

    Article  CAS  PubMed  Google Scholar 

  6. Steinberg D (2002) Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med 8(11):1211–1217

    Article  CAS  PubMed  Google Scholar 

  7. Glass CK, Witztum JL (2001) Atherosclerosis. The road ahead. Cell 104(4):503–516

    Article  CAS  PubMed  Google Scholar 

  8. Rifkind BM (1984) The lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA 251(3):351–364

    Article  Google Scholar 

  9. Varady KA, Wang Y, Jones PJ (2003) Role of policosanols in the prevention and treatment of cardiovascular disease. Nutr Rev 61(11):376–383

    Article  PubMed  Google Scholar 

  10. Zuo PY, Chen XL, Lei YH et al (2014) Growth arrest-specific gene 6 protein promotes the proliferation and migration of endothelial progenitor cells through the PI3K/AKT signaling pathway. Int J Mol Med 34(1):299–306

    CAS  PubMed  Google Scholar 

  11. Munoz-Chapuli R, Quesada AR, Angel MM (2004) Angiogenesis and signal transduction in endothelial cells. Cell Mol Life Sci 61(17):2224–2243

    Article  CAS  PubMed  Google Scholar 

  12. Thippeswamy G, Sheela ML, Salimath BP (2008) Octacosanol isolated from Tinospora cordifolia downregulates VEGF Gene expression by inhibiting nuclear translocation of NF-<kappa>B and its DNA binding activity. Eur J Pharmacol 588(2–3):141–150

    Article  CAS  PubMed  Google Scholar 

  13. Zhu M, Chen D, Li D et al (2013) Luteolin Inhibits angiotensin II-induced human umbilical vein endothelial cell proliferation and migration through downregulation of Src and Akt phosphorylation. Circ J 77:772–779

    Article  CAS  PubMed  Google Scholar 

  14. Safari E, Zavaran HA, hassan Z et al (2014) cytotoxic effect of immunotoxin containing the truncated form of pseudomonas exotoxin a and anti-VEGFR2 on HUVEC and MCF-7 cell lines. Cell J 16(2):203–210

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Giordano A, D’Angelillo A, Romano S et al (2014) Tirofiban induces VEGF production and stimulates migration and proliferation of endothelial cells. Vascul Pharmacol 61(2–3):63–71

    Article  CAS  PubMed  Google Scholar 

  16. Gallicchio M, Mitola S, Valdembri D et al (2005) Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor. Blood 105(5):1970–1976

    Article  CAS  PubMed  Google Scholar 

  17. Wang J, Yang Z, Wen J et al (2014) SKLB-M8 induces apoptosis through the AKT/mTOR signaling pathway in melanoma models and inhibits angiogenesis with decrease of ERK1/2 phosphorylation. J Pharmacol Sci 126(3):198–207

    Article  CAS  PubMed  Google Scholar 

  18. Jiang X, Tang X, Zhang P et al (2014) Cyanidin-3-O-beta-glucoside protects primary mouse hepatocytes against high glucose-induced apoptosis by modulating mitochondrial dysfunction and the PI3K/Akt pathway. Biochem Pharmacol 90(2):135–144

    Article  CAS  PubMed  Google Scholar 

  19. Mishra R, Kaur G (2013) Aqueous ethanolic extract of Tinospora cordifolia as a potential candidate for differentiation based therapy of glioblastomas. PLoS One 8(10):e78764

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Saha S, Ghosh S (2012) Tinospora cordifolia: one plant, many roles. Anc Sci Life 31(4):151–159

    Article  PubMed Central  PubMed  Google Scholar 

  21. Atchison N, Swindlehurst G, Papas KK et al (2014) Maintenance of ischemic beta cell viability through delivery of lipids and ATP by targeted liposomes. Biomater Sci 2(4):548–559

    Article  CAS  PubMed  Google Scholar 

  22. Morita T, Kitagawa M, Yamamoto S et al (2010) Activation of fibroblast and papilla cells by glycolipid biosurfactants, mannosylerythritol lipids. J Oleo Sci 59(8):451–455

    Article  CAS  PubMed  Google Scholar 

  23. Leite R, Webb RC (2001) Increased dilator response to heptanol and octanol in aorta from DOCA-salt-hypertensive rats. Pharmacology 62(1):29–35

    Article  CAS  PubMed  Google Scholar 

  24. Frantseva MV, Kokarovtseva L, Naus CG et al (2002) Specific gap junctions enhance the neuronal vulnerability to brain traumatic injury. J Neurosci 22(3):644–653

    CAS  PubMed  Google Scholar 

  25. Rami A, Volkmann T, Winckler J (2001) Effective reduction of neuronal death by inhibiting gap junctional intercellular communication in a rodent model of global transient cerebral ischemia. Exp Neurol 170(2):297–304

    Article  CAS  PubMed  Google Scholar 

  26. Andersson HC, Anderson MF, Porritt MJ et al (2011) Trauma-induced reactive gliosis is reduced after treatment with octanol and carbenoxolone. Neurol Res 33(6):614–624

    Article  CAS  PubMed  Google Scholar 

  27. Bosma M, Sidell N (1988) Retinoic acid inhibits Ca2+ currents and cell proliferation in a b-lymphocyte cell line. J Cell Physiol 135:317–323

    Article  CAS  PubMed  Google Scholar 

  28. Verhamme P, Hoylaerts MF (2006) The pivotal role of the endothelium in haemostasis and thrombosis. Acta Clin Belg 61(5):213–219

    Article  CAS  PubMed  Google Scholar 

  29. Barton M, Baretella O, Meyer MR (2012) Obesity and risk of vascular disease: importance of endothelium-dependent vasoconstriction. Br J Pharmacol 165(3):591–602

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Noa M, Mas R, Mesa R (1997) Effect of policosanol on circulating endothelial cells in experimental models in sprague-dawley rats and in rabbits. J Pharm Pharmacol 49(10):999–1002

    Article  CAS  PubMed  Google Scholar 

  31. Carbajal D, Molina V, Valdes S et al (1995) Anti-ulcer activity of higher primary alcohols of beeswax. J Pharm Pharmacol 47(9):731–733

    Article  CAS  PubMed  Google Scholar 

  32. Rajendran P, Rengarajan T, Thangavel J et al (2013) The vascular endothelium and human diseases. Int J Biol Sci 9(10):1057–1069

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Stancu CS, Toma L, Sima AV (2012) Dual role of lipoproteins in endothelial cell dysfunction in atherosclerosis. Cell Tissue Res 349(2):433–446

    Article  CAS  PubMed  Google Scholar 

  34. Inoue T, Croce K, Morooka T et al (2011) Vascular inflammation and repair: implications for re-endothelialization, restenosis, and stent thrombosis. JACC Cardiovasc Interv 4(10):1057–1066

    Article  PubMed Central  PubMed  Google Scholar 

  35. Gerber HP, McMurtrey A, Kowalski J et al (1998) Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. requirement for Flk-1/KDR activation. J Biol Chem 273(46):30336–30343

    Article  CAS  PubMed  Google Scholar 

  36. Shiojima I, Walsh K (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 90(12):1243–1250

    Article  CAS  PubMed  Google Scholar 

  37. Pugazhenthi S, Nesterova A, Sable C et al (2000) Akt/Protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 275(15):10761–10766

    Article  CAS  PubMed  Google Scholar 

  38. L’Hote CG, Knowles MA (2005) Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. Exp Cell Res 304(2):417–431

    Article  PubMed  Google Scholar 

  39. Corrigan CJ, Wang W, Meng Q et al (2011) T-helper cell type 2 (Th2) memory T cell-potentiating cytokine IL-25 has the potential to promote angiogenesis in asthma. Proc Natl Acad Sci USA 108(4):1579–1584

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Chen HF, Liu SJ, Chen G (2015) Heat shock protein 27 phosphorylation in the proliferation and apoptosis of human umbilical vein endothelial cells induced by high glucose through the phosphoinositide 3kinase/Akt and extracellular signalregulated kinase 1/2 pathways. Mol Med Rep 11:1504–1508

    CAS  PubMed  Google Scholar 

  41. Jang H, Oh MY, Kim YJ et al (2014) Hydrogen sulfide treatment induces angiogenesis after cerebral ischemia. J Neurosci Res 92(11):1520–1528

    Article  CAS  PubMed  Google Scholar 

  42. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation of China Grant 81370468/H2501.

Conflict of interest

The authors state that they have no conflicts of interest to disclosure.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Cheng-Yun Liu.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, YW., Zuo, PY., Zha, XN. et al. Octacosanol Enhances the Proliferation and Migration of Human Umbilical Vein Endothelial Cells via Activation of the PI3K/Akt and MAPK/Erk Pathways. Lipids 50, 241–251 (2015). https://doi.org/10.1007/s11745-015-3991-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-015-3991-2

Keywords

Navigation