Published online before print February 14, 2005, doi: 10.1161/01.CIR.0000155612.47040.17
(Circulation. 2005;111:926-931.)
© 2005 American Heart Association, Inc.
Vascular Medicine |
Potent Inhibitory Effect of Sirolimus on Circulating Vascular Progenitor Cells
From the Department of Cardiovascular Medicine (D.F., M.S., K.T., R.N.), University of Tokyo Graduate School of Medicine, Tokyo, Japan, and PRESTO (M.S.), Japan Science and Technology Agency Kawaguchi, Saitama, Japan
Correspondence to Masataka Sata, MD, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail msata-circ{at}umin.ac.jp
Received June 17, 2004; revision received October 5, 2004; accepted October 15, 2004.
Background— Neointimal hyperplasia is the major cause of in-stent restenosis (ISR). The sirolimus-eluting stent (SES) has emerged as a promising therapy to prevent ISR; however, the exact mechanism by which locally delivered sirolimus, an immunosuppressive agent, prevents ISR remains unknown. Recent evidence suggests that circulating progenitor cells may contribute to neointimal formation.
Methods and Results— Mononuclear cells (MNCs) were isolated from peripheral blood of healthy human volunteers. Smooth muscle (SM)–like cells outgrew from the culture of MNCs (1x106) in the presence of platelet-derived growth factor-BB and basic fibroblast growth factor, whereas endothelial cell–like cells were obtained in the presence of vascular endothelial growth factor. Sirolimus potently inhibited SM-like cell outgrowth. The number of SM-like cells was significantly reduced at a concentration as low as 0.1 ng/mL (15.9±5.8% of control, P<0.001). Sirolimus also exerted an inhibitory effect on endothelial cell–like cells that originated from MNCs. Wire-mediated vascular injury was induced in femoral arteries of bone marrow chimeric mice. Either vehicle or sirolimus was administered locally to the perivascular area of the injured arteries. Sirolimus significantly reduced neointima hyperplasia at 4 weeks (intima/media ratio 2.0±0.3 versus 1.0±0.2, P<0.05) with a decreased number of bone marrow–derived SM-like cells and hematopoietic cells in the lesion. Reendothelialization was retarded in the arteries treated with sirolimus.
Conclusions— The potent inhibitory effects of sirolimus on circulating smooth muscle progenitor cells may mediate the clinical efficacy of SES, at least in part. Sirolimus potentially may affect reendothelialization after stent implantation.
Key Words: stents • restenosis • balloon • atherosclerosis • endothelium
This article has been cited by other articles:
 |
|
 |
|
  M. Mutsuga, Y. Narita, A. Yamawaki, M. Satake, H. Kaneko, Y. Suematsu, A. Usui, and Y. Ueda A new strategy for prevention of anastomotic stricture using tacrolimus-eluting biodegradable nanofiber. J. Thorac. Cardiovasc. Surg., March 1, 2009; 137(3): 703 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Hegner, M. Lange, A. Kusch, K. Essin, O. Sezer, E. Schulze-Lohoff, F. C. Luft, M. Gollasch, and D. Dragun mTOR Regulates Vascular Smooth Muscle Cell Differentiation From Human Bone Marrow-Derived Mesenchymal Progenitors Arterioscler Thromb Vasc Biol, February 1, 2009; 29(2): 232 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cutler, K. Stevenson, H. T. Kim, P. Richardson, V. T. Ho, E. Linden, C. Revta, R. Ebert, D. Warren, S. Choi, et al. Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation Blood, December 1, 2008; 112(12): 4425 - 4431. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. I. Hamilos, M. Ostojic, B. Beleslin, D. Sagic, L. Mangovski, S. Stojkovic, M. Nedeljkovic, D. Orlic, B. Milosavljevic, D. Topic, et al. Differential effects of drug-eluting stents on local endothelium-dependent coronary vasomotion. J. Am. Coll. Cardiol., June 3, 2008; 51(22): 2123 - 2129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, R. Jabara, L. Pendyala, Y. Otsuka, T. Shinke, D. Hou, K. Robinson, and N. Chronos Abnormal Vasomotor Function of Porcine Coronary Arteries Distal to Sirolimus-Eluting Stents J. Am. Coll. Cardiol. Intv., June 1, 2008; 1(3): 279 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Tanaka, M. Sata, T. Natori, J.-r. Kim-Kaneyama, K. Nose, M. Shibanuma, Y. Hirata, and R. Nagai Circulating progenitor cells contribute to neointimal formation in nonirradiated chimeric mice FASEB J, February 1, 2008; 22(2): 428 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. G. Nuhrenberg, N. Langwieser, J. B.K. Schwarz, Y. Hou, P. Frank, F. Sorge, S. Matschurat, S. Seidl, A. Kastrati, A. Schomig, et al. EMAP-II downregulation contributes to the beneficial effects of rapamycin after vascular injury Cardiovasc Res, February 1, 2008; 77(3): 580 - 589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamada, T. Kondo, Y. Numaguchi, M. Tsuzuki, T. Matsubara, I. Manabe, M. Sata, R. Nagai, and T. Murohara Angiotensin II Receptor Blocker Inhibits Neointimal Hyperplasia Through Regulation of Smooth Muscle Like Progenitor Cells Arterioscler Thromb Vasc Biol, November 1, 2007; 27(11): 2363 - 2369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Reddy, J. K. Vasir, G. V. Hegde, S. S. Joshi, and V. Labhasetwar Erythropoietin Induces Excessive Neointima Formation: A Study in a Rat Carotid Artery Model of Vascular Injury Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2007; 12(3): 237 - 247. [Abstract] [PDF]
|
|
|
|
|
|
P. Meier and C. Seiler Reply J. Am. Coll. Cardiol., August 7, 2007; 50(6): 561 - 561. [Full Text] [PDF]
|
|
|
|
|
|
A. V. Finn, G. Nakazawa, M. Joner, F. D. Kolodgie, E. K. Mont, H. K. Gold, and R. Virmani Vascular Responses to Drug Eluting Stents: Importance of Delayed Healing Arterioscler Thromb Vasc Biol, July 1, 2007; 27(7): 1500 - 1510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Inoue, M. Sata, Y. Hikichi, R. Sohma, D. Fukuda, T. Uchida, M. Shimizu, H. Komoda, and K. Node Mobilization of CD34-Positive Bone Marrow-Derived Cells After Coronary Stent Implantation: Impact on Restenosis Circulation, February 6, 2007; 115(5): 553 - 561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Pislaru, A. Harbuzariu, R. Gulati, T. Witt, N. P. Sandhu, R. D. Simari, and G. S. Sandhu Magnetically Targeted Endothelial Cell Localization in Stented Vessels J. Am. Coll. Cardiol., November 7, 2006; 48(9): 1839 - 1845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Futamatsu, M. Sabate, D. J. Angiolillo, P. Jimenez-Quevedo, C. Corros, K. Morikawa-Futamatsu, F. Alfonso, J. Jiang, P. Cervinka, R. Hernandez-Antolin, et al. Characterization of Plaque Prolapse After Drug-Eluting Stent Implantation in Diabetic Patients: A Three-Dimensional Volumetric Intravascular Ultrasound Outcome Study J. Am. Coll. Cardiol., September 19, 2006; 48(6): 1139 - 1145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Zhang, D. Su, S. Qu, T. Tse, R. Bottino, A.N. Balamurugan, J. Xu, J. S. Bromberg, and H. H. Dong Sirolimus Is Associated With Reduced Islet Engraftment and Impaired {beta}-Cell Function Diabetes, September 1, 2006; 55(9): 2429 - 2436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Cho, T.-Y. Kim, H.-J. Cho, K.-W. Park, S.-Y. Zhang, J.-H. Kim, S.-H. Kim, J.-Y. Hahn, H.-J. Kang, Y.-B. Park, et al. The Effect of Stem Cell Mobilization by Granulocyte-Colony Stimulating Factor on Neointimal Hyperplasia and Endothelial Healing After Vascular Injury With Bare-Metal Versus Paclitaxel-Eluting Stents J. Am. Coll. Cardiol., July 18, 2006; 48(2): 366 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Roy-Chaudhury, V. P. Sukhatme, and A. K. Cheung Hemodialysis Vascular Access Dysfunction: A Cellular and Molecular Viewpoint J. Am. Soc. Nephrol., April 1, 2006; 17(4): 1112 - 1127. [Abstract] [Full Text] [PDF]
|
|