Circulation. 2002;105:3017-3024
Published online before print May 20, 2002, doi: 10.1161/01.CIR.0000018166.84319.55
Published online before print May 20, 2002, doi: 10.1161/01.CIR.0000018166.84319.55
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(Circulation. 2002;105:3017.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Statin Therapy Accelerates Reendothelialization
A Novel Effect Involving Mobilization and Incorporation of Bone Marrow-Derived Endothelial Progenitor Cells
From the Department of Medicine (Cardiovascular Research), St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass.
Correspondence to Takayuki Asahara, MD, PhD, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail asa777@ aol.com
Background— Primary and secondary prevention trials suggest that statins possess favorable effects independent of cholesterol reduction. We investigated whether statin therapy may also accelerate reendothelialization after carotid balloon injury.
Methods and Results— Simvastatin treatment in 34 male Sprague-Dawley rats accelerated reendothelialization of the balloon-injured arterial segments (reendothelialized area at 2 weeks, 12.3±1.8 versus 5.4±1.1 mm2, P< 0.01) and resulted in a dose-dependent (0.2 or 1 mg/kg IP) significant reduction in neointimal thickening at 2, 3, and 4 weeks compared with saline-injected controls (n=18). To elucidate the mechanism, we investigated the contribution of bone marrow–derived endothelial progenitor cells (EPCs) by bone marrow transplantation from Tie2/lacZ mice to background mice or nude rats. X-gal staining of mouse carotid artery specimens revealed a 2.9-fold increase in the number of ß-gal–positive cells per square millimeter appearing on the carotid artery luminal surface at 2 weeks, and double-fluorescence immunohistochemistry disclosed a significant 5-fold increase in the number of double-positive cells (ß-gal, isolectin B4) on the luminal surface in carotid arteries of statin-treated nude rats (20±3 versus 4±1 cells/mm surface length, P<0.005). Statins increased circulating rat EPCs (2.4-fold at 2 weeks and 2.5-fold at 4 weeks, P<0.001) and induced adhesiveness of cultured human EPCs by upregulation of the integrin subunits 
5, ß1, v, and ß5 of human EPCs as shown by reverse transcription–polymerase chain reaction and fluorescence-activated cell sorting.
Conclusions— These findings establish additional mechanisms by which statins may specifically preempt disordered vascular wall pathology and constitute physiological evidence that EPC mobilization represents a functionally relevant consequence of statin therapy.
Key Words: coronary disease • endothelium • angiogenesis • statins • cells
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V. Fuster, P. R. Moreno, Z. A. Fayad, R. Corti, and J. J. Badimon Atherothrombosis and High-Risk Plaque: Part I: Evolving Concepts J. Am. Coll. Cardiol., September 20, 2005; 46(6): 937 - 954. [Abstract] [Full Text] [PDF]
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 J. Sugawara, M. Mitsui-Saito, C. Hayashi, T. Hoshiai, M. Senoo, H. Chisaka, N. Yaegashi, and K. Okamura Decrease and Senescence of Endothelial Progenitor Cells in Patients with Preeclampsia J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5329 - 5332. [Abstract] [Full Text] [PDF]
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A. Leri and J. Kajstura Endothelial Progenitor Cells: Unexpected Disclosures Circ. Res., August 19, 2005; 97(4): 299 - 301. [Full Text] [PDF]
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 Y. J. Woo, T. J. Grand, M. F. Berry, P. Atluri, M. A. Moise, V. M. Hsu, J. Cohen, O. Fisher, J. Burdick, M. Taylor, et al. Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy J. Thorac. Cardiovasc. Surg., August 1, 2005; 130(2): 321 - 329. [Abstract] [Full Text] [PDF]
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J. I. Rotmans, J. M.M. Heyligers, H. J.M. Verhagen, E. Velema, M. M. Nagtegaal, D. P.V. de Kleijn, F. G. de Groot, E. S.G. Stroes, and G. Pasterkamp In Vivo Cell Seeding With Anti-CD34 Antibodies Successfully Accelerates Endothelialization but Stimulates Intimal Hyperplasia in Porcine Arteriovenous Expanded Polytetrafluoroethylene Grafts Circulation, July 5, 2005; 112(1): 12 - 18. [Abstract] [Full Text] [PDF]
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C. Schmidt-Lucke, L. Rossig, S. Fichtlscherer, M. Vasa, M. Britten, U. Kamper, S. Dimmeler, and A. M. Zeiher Reduced Number of Circulating Endothelial Progenitor Cells Predicts Future Cardiovascular Events: Proof of Concept for the Clinical Importance of Endogenous Vascular Repair Circulation, June 7, 2005; 111(22): 2981 - 2987. [Abstract] [Full Text] [PDF]
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G. P. Fadini, C. Agostini, A. Avogaro, U. Ghani, A. Shuaib, A. Salam, A. Nasir, U. Shuaib, T. Jeerakathil, F. Sher, et al. Endothelial Progenitor Cells in Cerebrovascular Disease * Response: Stroke, June 1, 2005; 36(6): 1112 - 1113. [Full Text] [PDF]
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U. Landmesser, F. Bahlmann, M. Mueller, S. Spiekermann, N. Kirchhoff, S. Schulz, C. Manes, D. Fischer, K. de Groot, D. Fliser, et al. Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans Circulation, May 10, 2005; 111(18): 2356 - 2363. [Abstract] [Full Text] [PDF]
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C. Heiss, S. Keymel, U. Niesler, J. Ziemann, M. Kelm, and C. Kalka Impaired Progenitor Cell Activity in Age-Related Endothelial Dysfunction J. Am. Coll. Cardiol., May 3, 2005; 45(9): 1441 - 1448. [Abstract] [Full Text] [PDF]
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C. Dong, L. E. Crawford, and P. J. Goldschmidt-Clermont Endothelial Progenitor Obsolescence and Atherosclerotic Inflammation J. Am. Coll. Cardiol., May 3, 2005; 45(9): 1458 - 1460. [Full Text] [PDF]
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 P. N. Kao Simvastatin Treatment of Pulmonary Hypertension: An Observational Case Series Chest, April 1, 2005; 127(4): 1446 - 1452. [Abstract] [Full Text] [PDF]
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E. O. Weinberg, M. Scherrer-Crosbie, M. H. Picard, B. A. Nasseri, C. MacGillivray, J. Gannon, Q. Lian, K. D. Bloch, and R. T. Lee Rosuvastatin reduces experimental left ventricular infarct size after ischemia-reperfusion injury but not total coronary occlusion Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1802 - H1809. [Abstract] [Full Text] [PDF]
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J. Sugawara, M. Mitsui-Saito, T. Hoshiai, C. Hayashi, Y. Kimura, and K. Okamura Circulating Endothelial Progenitor Cells during Human Pregnancy J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1845 - 1848. [Abstract] [Full Text] [PDF]
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V. Schachinger and A. M. Zeiher Stem Cells and Cardiovascular and Renal Disease: Today and Tomorrow J. Am. Soc. Nephrol., March 1, 2005; 16(3_suppl_1): S2 - S6. [Abstract] [Full Text] [PDF]
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 L. G. Futterman and L. Lemberg Cardiac Repair With Autologous Bone Marrow Stem Cells Am. J. Crit. Care., November 1, 2004; 13(6): 512 - 518. [Full Text] [PDF]
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