American Journal of Clinical Medicine Research
ISSN (Print): 2328-4005 ISSN (Online): 2328-403X Website: Editor-in-chief: Dario Galante
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American Journal of Clinical Medicine Research. 2015, 3(4), 70-76
DOI: 10.12691/ajcmr-3-4-3
Open AccessArticle

Effect of Different Doses of Atorvastatin Therapy on Endothelial Progenitor Cells and Angiogenic Factors in Patients with Ischemic Heart Disease

Igor V. Sergienko1, , Alexey A. Ansheles2 and Oxana M. Drapkina3

1Department of atherosclerosis, Russian Cardiology Research Center, Moscow, Russian Federation

2Department of nuclear diagnostics, Russian Cardiology Research Center, Moscow, Russian Federation

3National Research Center for Preventive Medicine, Moscow, Russian Federation

Pub. Date: November 10, 2015

Cite this paper:
Igor V. Sergienko, Alexey A. Ansheles and Oxana M. Drapkina. Effect of Different Doses of Atorvastatin Therapy on Endothelial Progenitor Cells and Angiogenic Factors in Patients with Ischemic Heart Disease. American Journal of Clinical Medicine Research. 2015; 3(4):70-76. doi: 10.12691/ajcmr-3-4-3


Aim. The purpose of current research was to assess changes in endothelial progenitor cells (EPC) counts and angiogenic factors levels during atorvastatin therapy in different doses in patients with ischemic heart disease (IHD) as an independent predictor of cardiovascular morbidity and mortality. Methods and Results. The main group included 58 patients with IHD during atorvastatin therapy. EPC quantity (CD34+/CD133+/CD309+ phenotype) was measured by flow cytometry two times – before treatment and 3 months after. Vascular endothelial growth factor (VEGF), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), endostatin levels and lipid profile were also measured twice. The control group consisted of 15 healthy volunteers with the same analyzes performed once. Atorvastatin therapy in IHD patients within three months of treatment caused a significant (72% on average) increase of EPC counts (p<0.05). Dependence of EPC gain on statin dose was not reliable (p=0.10), but it was higher when initial EPC counts were low (p=0.01). The therapy showed reliable reduction of VEGF level (by 11%, p<0.01), CRP – by 26% (p<0.01), total cholesterol (TCh) – by 30% (p<0.01), low density lipoprotein (LDL-C) – by 35% (p<0.01), triglycerides (TG) – by 18% (p<0.01), while endostatin, MCP-1 and high density lipoprotein (HDL-C) levels did not change. Correlations between the EPC, TCh and LDL-C changes during therapy were revealed: higher EPC counts gain was associated with higher TCh (p=-0.37, r<0.01) and LDL-C (p=-0.41, r<0.01) levels decrease. Conclusion. We found a significant increase of EPC counts in IHD patients when treated with atorvastatin for 3 months, without statistically reliable difference depending on dosage.

endothelial progenitor cells ischemic heart disease atorvastatin angiogenic growth factors

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[1]  van Os R., Kamminga L.M., de Haan G. Stem cell assays: something old, something new, something borrowed. Stem Cells. 2004. 22(7): 1181-1190.
[2]  Xu Q. Stem cells and transplant arteriosclerosis. Circ Res. 2008. 102(9): 1011-1024.
[3]  Xu Q. The impact of progenitor cells in atherosclerosis. Nat Clin Pract Cardiovasc Med. 2006. 3(2): 94-101.
[4]  Hirschi K.K., Ingram D.A., Yoder M.C. Assessing identity, phenotype, and fate of endothelial progenitor cells. Arterioscler Thromb Vasc Biol. 2008. 28(9): 1584-1595.
[5]  Zampetaki A., Kirton J.P., Xu Q. Vascular repair by endothelial progenitor cells. Cardiovasc Res. 2008. 78(3): 413-421.
[6]  Tepper O.M., Capla J.M., Galiano R.D., Ceradini D.J., Callaghan M.J., Kleinman M.E., Gurtner G.C. Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. Blood. 2005. 105(3): 1068-1077.
[7]  Reyes M., Dudek A., Jahagirdar B., Koodie L., Marker P.H., Verfaillie C.M. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest. 2002. 109(3): 337-346. PMCID: 150857.
[8]  Takahashi T., Kalka C., Masuda H., Chen D., Silver M., Kearney M., Magner M., Isner J.M., Asahara T. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 1999. 5(4): 434-438.
[9]  Asahara T., Murohara T., Sullivan A., Silver M., van der Zee R., Li T., Witzenbichler B., Schatteman G., Isner J.M. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997. 275(5302): 964-967.
[10]  Schmidt-Lucke C., Rossig L., Fichtlscherer S., Vasa M., Britten M., Kamper U., Dimmeler S., Zeiher A.M. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation. 2005. 111(22): 2981-2987.
[11]  Werner N., Nickenig G. Influence of cardiovascular risk factors on endothelial progenitor cells: limitations for therapy? Arterioscler Thromb Vasc Biol. 2006. 26(2): 257-266.
[12]  Yoder M.C. Defining human endothelial progenitor cells. J Thromb Haemost. 2009. 7 Suppl 1: 49-52.
[13]  Gallacher L., Murdoch B., Wu D.M., Karanu F.N., Keeney M., Bhatia M. Isolation and characterization of human CD34(-)Lin(-) and CD34(+)Lin(-) hematopoietic stem cells using cell surface markers AC133 and CD7. Blood. 2000. 95(9): 2813-2820.
[14]  Hill J.M., Zalos G., Halcox J.P., Schenke W.H., Waclawiw M.A., Quyyumi A.A., Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003. 348(7): 593-600.
[15]  Schmeisser A., Garlichs C.D., Zhang H., Eskafi S., Graffy C., Ludwig J., Strasser R.H., Daniel W.G. Monocytes coexpress endothelial and macrophagocytic lineage markers and form cord-like structures in Matrigel under angiogenic conditions. Cardiovasc Res. 2001. 49(3): 671-680.
[16]  Fujiyama S., Amano K., Uehira K., Yoshida M., Nishiwaki Y., Nozawa Y., Jin D., Takai S., Miyazaki M., Egashira K., Imada T., Iwasaka T., Matsubara H. Bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-dependent manner and accelerate reendothelialization as endothelial progenitor cells. Circ Res. 2003. 93(10): 980-989.
[17]  Krause D.S., Fackler M.J., Civin C.I., May W.S. CD34: structure, biology, and clinical utility. Blood. 1996. 87(1): 1-13.
[18]  Shalaby F., Ho J., Stanford W.L., Fischer K.D., Schuh A.C., Schwartz L., Bernstein A., Rossant J. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell. 1997. 89(6): 981-990.
[19]  Friedrich E.B., Walenta K., Scharlau J., Nickenig G., Werner N. CD34-/CD133+/VEGFR-2+ endothelial progenitor cell subpopulation with potent vasoregenerative capacities. Circ Res. 2006. 98(3): e20-25.
[20]  Aicher A., Heeschen C., Mildner-Rihm C., Urbich C., Ihling C., Technau-Ihling K., Zeiher A.M., Dimmeler S. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med. 2003. 9(11): 1370-1376.
[21]  Zhang Q., Yin H., Liu P., Zhang H., She M. Essential role of HDL on endothelial progenitor cell proliferation with PI3K/Akt/cyclin D1 as the signal pathway. Exp Biol Med (Maywood). 2010. 235(9): 1082-1092.
[22]  Poltorak Z., Cohen T., Sivan R., Kandelis Y., Spira G., Vlodavsky I., Keshet E., Neufeld G. VEGF145, a secreted vascular endothelial growth factor isoform that binds to extracellular matrix. J Biol Chem. 1997. 272(11): 7151-7158.
[23]  Rissanen T.T., Markkanen J.E., Gruchala M., Heikura T., Puranen A., Kettunen M.I., Kholova I., Kauppinen R.A., Achen M.G., Stacker S.A., Alitalo K., Yla-Herttuala S. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res. 2003. 92(10): 1098-1106.
[24]  Lin J., Kakkar V., Lu X. Impact of MCP-1 in atherosclerosis. Curr Pharm Des. 2014. 20(28): 4580-4588.
[25]  Cavalera M., Frangogiannis N.G. Targeting the chemokines in cardiac repair. Curr Pharm Des. 2014. 20(12): 1971-1979.
[26]  Yadav A., Saini V., Arora S. MCP-1: chemoattractant with a role beyond immunity: a review. Clin Chim Acta. 2010. 411(21-22): 1570-1579.
[27]  Hanahan D., Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996. 86(3): 353-364.
[28]  Rehn M., Pihlajaniemi T. Alpha 1(XVIII), a collagen chain with frequent interruptions in the collagenous sequence, a distinct tissue distribution, and homology with type XV collagen. Proc Natl Acad Sci U S A. 1994. 91(10): 4234-4238. PMCID: 43759.
[29]  Fu Y., Wu X., Han Q., Liang Y., He Y., Luo Y. Sulfate stabilizes the folding intermediate more than the native structure of endostatin. Arch Biochem Biophys. 2008. 471(2): 232-239.
[30]  Rohde E., Malischnik C., Thaler D., Maierhofer T., Linkesch W., Lanzer G., Guelly C., Strunk D. Blood monocytes mimic endothelial progenitor cells. Stem Cells. 2006. 24(2): 357-367.
[31]  Ruda M.M., Aref'eva T.I., Tripoten M.I., Balakhonova T.V., Parfenova E.V., Karpov Iu A. [Circulating endothelial progenitor cells and vascular endothelial dysfunction]. Ross Fiziol Zh Im I M Sechenova. 2009. 95(6): 545-562.
[32]  Sergienko I.V., Masenko V.P., Semenova A.E., Gabrusenko S.A., Naumov V.G., Belenkov Y.N. The impact of revascularization on the dynamics of angiogenic factors in patients with coronary heart disease. Kardiologia. 2009. 12: 4-10.
[33]  Petit I., Jin D., Rafii S. The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol. 2007. 28(7): 299-307. PMCID: 2952492.
[34]  Henrich D., Seebach C., Wilhelm K., Marzi I. High dosage of simvastatin reduces TNF-alpha-induced apoptosis of endothelial progenitor cells but fails to prevent apoptosis induced by IL-1beta in vitro. J Surg Res. 2007. 142(1): 13-19.
[35]  Vasa M., Fichtlscherer S., Adler K., Aicher A., Martin H., Zeiher A.M., Dimmeler S. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation. 2001. 103(24): 2885-2890.
[36]  Mangialardi G., Monopoli A., Ongini E., Spinetti G., Fortunato O., Emanueli C., Madeddu P. Nitric oxide-donating statin improves multiple functions of circulating angiogenic cells. Br J Pharmacol. 2011. 164(2b): 570-583. PMCID: 3188894.
[37]  Psaltis P.J., Simari R.D. Vascular Wall Progenitor Cells in Health and Disease. Circ Res. 2015. 116(8): 1392-1412.
[38]  Ye H., He F., Fei X., Lou Y., Wang S., Yang R., Hu Y., Chen X. High-dose atorvastatin reloading before percutaneous coronary intervention increased circulating endothelial progenitor cells and reduced inflammatory cytokine expression during the perioperative period. J Cardiovasc Pharmacol Ther. 2014. 19(3): 290-295.
[39]  Banerjee S., Abu Fadel M., Sarode R., Terada L., Moritz T., Luo P., Hastings J., Brilakis E.S., Reda D. Plaque regression and progenitor cell mobilization with intensive lipid elimination regimen (PREMIER) trial design. J Clin Apher. 2014. 29(2): 97-106.
[40]  Hibbert B., Simard T., Ramirez F.D., Pourdjabbar A., Raizman J.E., Maze R., Wilson K.R., Hawken S., O'Brien E.R. The effect of statins on circulating endothelial progenitor cells in humans: a systematic review. J Cardiovasc Pharmacol. 2013. 62(5): 491-496.
[41]  Clem J.R., Strain J.D., Farver D.K. Individualized initiation of statin therapy determined by baseline LDL-C: Are you more likely to achieve goal LDL-C? Risk Manag Healthc Policy. 2010. 3: 1-11. PMCID: 3270916.
[42]  Di Sciascio G., Patti G., Pasceri V., Gaspardone A., Colonna G., Montinaro A. Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) Randomized Trial. J Am Coll Cardiol. 2009. 54(6): 558-565.
[43]  Eisen A., Leshem-Lev D., Yavin H., Orvin K., Mager A., Rechavia E., Bental T., Dadush O., Battler A., Kornowski R., Lev E.I. Effect of High Dose Statin Pretreatment on Endothelial Progenitor Cells After Percutaneous Coronary Intervention (HIPOCRATES Study). Cardiovasc Drugs Ther. 2015.
[44]  Waters D.D., Guyton J.R., Herrington D.M., McGowan M.P., Wenger N.K., Shear C. Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol. 2004. 93(2): 154-158.
[45]  Pedersen T.R., Faergeman O., Kastelein J.J., Olsson A.G., Tikkanen M.J., Holme I., Larsen M.L., Bendiksen F.S., Lindahl C., Szarek M., Tsai J. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005. 294(19): 2437-2445.
[46]  Antonio N., Fernandes R., Soares A., Soares F., Lopes A., Carvalheiro T., Paiva A., Pego G.M., Providencia L.A., Goncalves L., Ribeiro C.F. Impact of prior chronic statin therapy and high-intensity statin therapy at discharge on circulating endothelial progenitor cell levels in patients with acute myocardial infarction: a prospective observational study. Eur J Clin Pharmacol. 2014. 70(10): 1181-1193.
[47]  Pesaro A.E., Serrano C.V., Jr., Katz M., Marti L., Fernandes J.L., Parra P.R., Campos A.H. Increasing doses of simvastatin versus combined ezetimibe/simvastatin: effect on circulating endothelial progenitor cells. J Cardiovasc Pharmacol Ther. 2013. 18(5): 447-452.