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.
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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
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
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
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
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
Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362(6423):801–809
Steinberg D (2002) Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime. Nat Med 8(11):1211–1217
Glass CK, Witztum JL (2001) Atherosclerosis. The road ahead. Cell 104(4):503–516
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
Varady KA, Wang Y, Jones PJ (2003) Role of policosanols in the prevention and treatment of cardiovascular disease. Nutr Rev 61(11):376–383
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
Munoz-Chapuli R, Quesada AR, Angel MM (2004) Angiogenesis and signal transduction in endothelial cells. Cell Mol Life Sci 61(17):2224–2243
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
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
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
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
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
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
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
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
Saha S, Ghosh S (2012) Tinospora cordifolia: one plant, many roles. Anc Sci Life 31(4):151–159
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
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
Leite R, Webb RC (2001) Increased dilator response to heptanol and octanol in aorta from DOCA-salt-hypertensive rats. Pharmacology 62(1):29–35
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
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
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
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
Verhamme P, Hoylaerts MF (2006) The pivotal role of the endothelium in haemostasis and thrombosis. Acta Clin Belg 61(5):213–219
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
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
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
Rajendran P, Rengarajan T, Thangavel J et al (2013) The vascular endothelium and human diseases. Int J Biol Sci 9(10):1057–1069
Stancu CS, Toma L, Sima AV (2012) Dual role of lipoproteins in endothelial cell dysfunction in atherosclerosis. Cell Tissue Res 349(2):433–446
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
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
Shiojima I, Walsh K (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res 90(12):1243–1250
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
L’Hote CG, Knowles MA (2005) Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. Exp Cell Res 304(2):417–431
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
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
Jang H, Oh MY, Kim YJ et al (2014) Hydrogen sulfide treatment induces angiogenesis after cerebral ischemia. J Neurosci Res 92(11):1520–1528
Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473(7347):298–307
Acknowledgments
This study was supported by the National Natural Science Foundation of China Grant 81370468/H2501.
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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
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DOI: https://doi.org/10.1007/s11745-015-3991-2