(Circulation. 2001;104:852.)
© 2001 American Heart Association, Inc.
Editorial |
Bench to Bedside
The Development of Rapamycin and Its Application to Stent Restenosis
From the Center for Molecular Cardiology, Department of Pharmacology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.
Correspondence to Andrew R. Marks, MD, Center for Molecular Cardiology, Box 65, Columbia University College of Physicians and Surgeons, Room 9-401, 630 West 168th Street, New York, NY 10032. E-mail arm42{at}columbia.edu
Key Words: Editorials • stents • restenosis • signal transduction
In response to physiological stimuli (eg, wound healing), normally quiescent smooth muscle cells (SMCs) within the vessel wall can be activated to migrate and proliferate to produce new blood vessels. In addition to this physiological response, pathological migration and proliferation within the vessel wall can occur in disease states. Examples of such disease states include tumor growth and metastasis, diabetic retinopathy, arthritis, accelerated arteriopathy after cardiac transplantation, and neointimal proliferation after balloon angioplasty (PTCA) and stent placement. An important limitation of PTCA is restenosis, which is due in large part to luminal narrowing; restenosis occurs in 20% to 40% of patients within the first few months after a successful intervention.1,2 The percentage of patients that develop early restenosis after PTCA can be reduced by stent implantation. However, stents actually increase the amount of late luminal narrowing due to intimal hyperplasia,3 and the overall rate of stent restenosis remains unacceptably high (
30%).
Numerous pharmacological agents, including antiplatelet agents, anticoagulants, ACE inhibitors, and cytotoxic agents, have failed to adequately reduce restenosis after PTCA and stenting. Novel therapeutic approaches based on understanding the molecular mechanisms that cause intimal hyperplasia are needed to reduce the high incidence of stent restenosis. Arterial injury is associated with SMC activation and re-entry into the cell cycle. Multiple approaches to inhibiting SMC proliferation have been and are being evaluated. Gene delivery systems aimed at blocking SMC proliferation after PTCA have been tested4,5; however, the low efficiency and/or potential hazards of this approach may limit its usefulness. Radiation therapy has been evaluated in numerous studies and has shown considerable promise as a nonpharmacological, antiproliferative approach for the reduction of restenosis. However, significant side effects, including late stent thrombosis, may also limit its usefulness.6–8 The unusually late stent thrombosis seen in the patients treated with radiation therapy suggests that radiation may impair the ability of the vessel wall to endothelialize the stent struts.9
Recently, much attention has focused on the potential use of rapamycin (Sirolimus) to prevent stent restenosis. Rapamycin evolved from a failed antibiotic with no apparent therapeutic utility to its current status as a promising cardiovascular drug on the basis of a series of laboratory studies revealing that it is a potent inhibitor of both SMC proliferation and migration.10,11 Rapamycin, a macrolide antibiotic, is a natural fermentation product produced by Streptomyces hygroscopicus, which was originally identified in a soil sample from Rapa Nui (Easter Island) by the Canadian Medical Research Expedition (December 1964 through February 1965).12,13 Rapamycin was originally noted to have antifungal properties and, subsequently, its potent immunosuppressant properties (which made it unsuitable for use as an antibiotic) were appreciated.13 Largely because rapamycin was viewed as an immunosuppressant drug, its potential application for other therapeutic targets, including accelerated arteriopathy after cardiac transplantation and stent restenosis, remained underappreciated for almost a decade. The emergence of other promising anti-restenosis therapies further suppressed interest in rapamycin, despite accumulating in vitro evidence indicating that it has properties that are potentially ideally suited to attack important cardiovascular diseases.10,11,14–20
Rapamycin’s cellular actions are mediated by binding to its intracellular receptor, the FK506 binding protein (FKBP12), a member of the immunophilin family of proteins.21 The related immunosuppressant drug FK506 (tacrolimus) also binds to FKBP12, but this complex inhibits the phosphatase calcineurin. FK506-FKBP12 has no antiproliferative or antimigratory activity in vascular SMCs.10,11 Rapamycin-FKBP12 has no activity against calcineurin; rather, it inhibits a kinase called the target of rapamycin (TOR),22 which is a component in a pathway that regulates cell cycle progression (Figure 1). The finding that rapamycin inhibits multiple fundamental regulators of cell cycle progression in vascular SMCs suggested that it might have utility in the prevention of diseases linked to vascular SMC proliferation.10
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We and others demonstrated that rapamycin inhibits the proliferation of rodent and human vascular SMCs in vitro and porcine vascular SMCs in vivo by blocking cell cycle progression at the G1/S transition.10,16,19 These studies in vascular SMCs were based on earlier observations showing that the immunosuppressant activity of rapamycin was linked to its ability to inhibit cell cycle progression in T lymphocytes.23–25 In addition, we showed that rapamycin had the unexpected property of inhibiting vascular SMC migration: treating rat and human vascular SMCs with rapamycin (2 nmol/L) for 48 hours inhibited platelet-derived growth factor–induced migration in a modified Boyden chamber.11 These antiproliferative and antimigratory properties were specific to rapamycin; FK506 failed to inhibit either vascular SMC proliferation or migration. In fact, FK506 antagonizes rapamycin’s antiproliferative and antimigratory properties10,11 because both agents bind to the same cytosolic receptor, FKBP12.26 The findings that rapamycin possessed both antiproliferative and antimigratory properties led to the proposal that rapamycin should be tested in the treatment of disorders, such as accelerated arteriopathy, that occur in transplanted hearts and restenosis after PTCA and placement of coronary stents.10,11
Further investigation of the mechanisms by which rapamycin inhibits vascular SMC proliferation and migration provided additional support for its potential role as a cardiovascular therapeutic agent. Rapamycin-induced inhibition of vascular SMC proliferation is associated with a marked reduction in cyclin-dependent kinase (CDK) activity and a reduction in retinoblastoma protein phosphorylation.10 These actions of rapamycin in vascular SMCs are similar to its actions in other cell lines.25,27
The development of a rapamycin-resistant muscle cell line allowed us to elucidate the mechanism by which rapamycin inhibits vascular SMC proliferation. Using rapamycin-resistant muscle cell lines, we showed that the CDK inhibitor p27kip1 mediates rapamycin’s antiproliferative and antimigratory properties in muscle.17,20 Cell cycle arrest in some cell types is linked to elevation of p27kip1. p27kip1 increases in response to mitogen deprivation, cell-cell contact, or transforming growth factor-ß, whereas p27kip1 levels decrease in response to mitogens.28 Rapamycin inhibits mitogen-induced downregulation of p27kip1. 27 We showed that the defect in rapamycin-resistant muscle cells that allowed them to escape the antiproliferative effects of rapamycin was constitutively low levels of p27kip1 and the inability to increase p27kip1 in response to rapamycin.17 These findings were confirmed using cells from p27kip1-null mice29 that exhibited partial rapamycin resistance.17 Rapamycin also inhibits p70S6k phosphorylation and activity,30 as well as phosphorylation of the eukaryotic translation initiation factor 4E-binding protein in vascular SMCs.31
These findings suggested that part of the antiproliferative effect of rapamycin is linked to inhibition of protein translation. However, although rapamycin blocks phosphorylation of p70S6k in p27kip1-null cells17 and inhibits 4E-binding protein phosphorylation in the rapamycin-resistant muscle cells,32 the cells continue to proliferate. These findings further support the conclusion that it is the inability to elevate p27kip1 levels that attenuates the antiproliferative properties of rapamycin and that regulation of p27kip1 is a critical mechanism by which rapamycin inhibits vascular SMC growth. Moreover, we recently reported that the lack of p27kip1 also reduces rapamycin-mediated inhibition of vascular SMC migration, thus implying that p27kip1 has an important role in the signaling pathway(s) regulating SMC migration.20 In agreement with our studies, others have shown that overexpression of p27kip1 in SMCs inactivated cdk2 and cdk4 activity and that adenoviral gene transfer of p27kip1 after femoral artery balloon angioplasty significantly inhibited intimal cell proliferation.33
In September 1999, rapamycin was approved by the US Food and Drug Administration as an agent to prevent acute rejection in renal transplant patients. It is important to emphasize that the immunosuppressant activity of rapamycin is mediated through a mechanism distinct from that of FK506 and cyclosporine A (both of which inhibit calcineurin). The therapeutic benefits of both cyclosporine A and FK506 are limited, to some extent, by acute and chronic nephrotoxicity, which is believed to be linked to calcineurin inhibition. In contrast, because of its distinct mechanism of action, rapamycin use is not associated with nephrotoxicity.34 Regular administration of rapamycin (particularly in transplantation patients) produces other side effects in humans, including headaches, polyarthralgia, mild stomatitis, epistaxis, diarrhea, skin complaints, myelosuppression, hyperlipidemia, and overimmunosuppression.34,35
Indeed, the implantation of rapamycin-coated stents (BX Velocity) in de novo lesions was recently shown to be safe and effective in inhibiting neointimal formation36 in 30 patients with stable and unstable angina. Half of the patients received the fast-release formulation designed to deliver the drug (140 µg/cm2) within 15 days, and half received the slow-release formulation (
28 day drug release). Patients also received clopidogrel (75 mg/d) for 60 days after stent implantation. No patient approached >50% vessel narrowing by intravascular ultrasound or quantitative coronary angiography, and only 3 patients had >15% intimal hyperplasia by intravascular ultrasound at 4 months of follow-up.36 Although the number of patients studied was small, no edge restenosis or stent thrombosis was observed, both of which have been reported in studies of patients undergoing radiation therapy during coronary intervention.8,37 No adverse events were reported after 8 months of follow-up.36 Similar results were observed for both release formulations, although preliminary results suggest that the excessive proliferation and migration of vascular SMCs after coronary intervention can be prevented with 
15 days of intracoronary rapamycin exposure.36 At longer follow-up (6 months in 13 patients treated in Rotterdam and 12 months in 27 patients treated in Sao Paulo), the reduction in ultrasound-measured intimal hyperplasia in patients treated with rapamycin-coated stents persisted.38,39 These data suggest that rapamycin may provide protection against intimal hyperplasia after stent implantation in coronary arteries and, potentially, in peripheral arteries, without the complications seen with other modalities that reduce the incidence of restenosis.
The use of rapamycin to prevent chronic graft vascular disease (CGVD) or accelerated arteriopathy, especially after cardiac transplantation, may be an additional target for the drug’s antiproliferative and antimigratory properties. CGVD is marked by progressive development of coronary artery narrowing (concentric neointimal hyperplasia), possibly due to an ill-defined immunological response. Despite immunosuppression with cyclosporine A or FK506, CGVD persists, as manifested as progressive narrowing of the coronary arteries in the transplanted heart in a diffuse pattern that occurs in up to 75% of patients within the first year and affects virtually 100% of patients by year 4 to 5 after cardiac transplantation.40 Rapamycin’s potent immunosuppressive properties and the findings that rapamycin, but not FK506, inhibited vascular SMC proliferation and migration in vitro suggest that rapamycin would be the agent of choice for immunosuppression in cardiac transplantation patients.10,41 Moreover, rapamycin reversed the development of CGVD in a rodent heart allograft model.42 Indeed, rapamycin and the closely related compound 40-O-(2-hydroxyethyl) RAD (everolimus) are currently being investigated in clinical trials to determine whether they can inhibit intimal hyperplasia in cardiac transplant recipients.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or the American Heart Association.
References
1. Nobuyoshi M, Kimura T, Nosaka H, et al. Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. J Am Coll Cardiol. 1988; 12: 616–623.[Abstract]
2.
Serruys PW, Luijten HE, Beatt KJ, et al. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon: a quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation. 1988; 77: 361–371.
3.
Kuntz RE, Baim DS. Prevention of coronary restenosis: the evolving evidence base for radiation therapy. Circulation. 2000; 101: 2130–2133.
4.
Ohno T, Gordon D, San H, et al. Gene therapy for vascular smooth muscle cell proliferation after arterial injury. Science. 1994; 265: 781–784.
5.
Chang MW, Barr E, Seltzer J, et al. Cytostatic gene therapy for vascular proliferative disorders with a constitutively active form of the retinoblastoma gene product. Science. 1995; 267: 518–522.
6.
Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med. 1997; 336: 1697–1703.
7.
Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting: stent anticoagulation restenosis study investigators. N Engl J Med. 1998; 339: 1665–1671.
8.
Costa MA, Sabat M, van der Giessen WJ, et al. Late coronary occlusion after intracoronary brachytherapy. Circulation. 1999; 100: 789–792.
9.
Waksman R. Late thrombosis after radiation: sitting on a time bomb. Circulation. 1999; 100: 780–782.
10.
Marx SO, Jayaraman T, Go LO, et al. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res. 1995; 76: 412–417.
11. Poon M, Marx SO, Gallo R, et al. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest. 1996; 98: 2277–2283.[Medline] [Order article via Infotrieve]
12. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic, I: toxoneme of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo). 1975; 28: 721–726.[Medline] [Order article via Infotrieve]
13. Sehgal SN, Baker H, Vezina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo). 1975; 28: 727–732.[Medline] [Order article via Infotrieve]
14.
Jayaraman T, Marks AR. Rapamycin-FKBP12 blocks proliferation, induces differentiation, and inhibits cdc2 kinase activity in a myogenic cell line. J Biol Chem. 1993; 268: 25385–25388.
15. Gregory C, Huie P, Shorthouse R, et al. Treatment with rapamycin blocks arterial intimal thickening following mechanical and alloimmune injury. Transplantation Proc. 1993; 25: 120–121.[Medline] [Order article via Infotrieve]
16. Morris R, Cao W, Huang X, et al. Rapamycin (sirolimus) inhibits vascular smooth muscle cell DNA synthesis in vitro and suppresses narrowing in arterial allografts and in balloon-injured carotid arteries: evidence that rapamycin antagonizes growth factor action on immune and nonimmune cells. Transplant Proc. 1995; 27: 430–431.[Medline] [Order article via Infotrieve]
17. Luo Y, Marx SO, Kiyokawa H, et al. Rapamycin resistance tied to defective regulation of p27Kip1. Mol Cell Biol. 1996; 16: 6744–6751.[Abstract]
18. Marks AR. Attacking heart disease with novel molecular tools. Bull N Y Acad Med. 1996; 73: 25–36.[Medline] [Order article via Infotrieve]
19.
Gallo R, Padurean A, Chesebro JH, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by rapamycin. Circulation. 1998; 99: 2164–2170.
20.
Sun J, Marx SO, Chen H-J, et al. A role for p27Kip1 in vascular smooth muscle cell migration. Circulation. 2001; 103: 2967–2972.
21.
Marks AR. Cellular functions of immunophilins. Physiol Rev. 1996; 76: 631–649.
22.
Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science. 1991; 253: 905–909.
23.
Bierer BE, Mattilia PS, Standaert R, et al. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc Natl Acad Sci U S A. 1990; 87: 9231–9235.
24. Dumont FJ, Staruch MJ, Kooprak SL, et al. Distinct mechanisms of suppression of murine T-cell activation by the related macrolides FK-506 and rapamycin. J Immunol. 1990; 144: 251–258.[Abstract]
25.
Morice WG, Brunn GJ, Wiederrecht G, et al. Rapamycin-induced inhibition of p34cdc2 kinase activation is associated with G1/S-phase growth arrest in T lymphocytes. J Biol Chem. 1993; 268: 3734–3738.
26.
Schreiber S. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science. 1991; 251: 283–287.
27. Nourse J, Firpo E, Flanagan WM, et al. Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature. 1994; 372: 570–573.[Medline] [Order article via Infotrieve]
28.
Polyak K, Kato J-Y, Solomon MJ, et al. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-ß and contact inhibition to cell cycle arrest. Genes Dev. 1994; 8: 9–22.
29. Kiyokawa H, Kineman RD, Manova-Todoorova KO, et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27kip1. Cell. 1996; 85: 721–732.[Medline] [Order article via Infotrieve]
30.
Price DJ, Grove JR, Calvo V, et al. Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science. 1992; 257: 973–977.
31.
Graves LM, Bornfeldt KE, Argast GM, et al. cAMP- and rapamycin-sensitive regulation of the association of eukaryotic initiation factor 4E and the translational repressor PHAS-I in aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1995; 92: 7222–7226.
32.
Marx SO, Marks AR. Cell cycle progression and proliferation despite 4BP-1 dephosphorylation. Mol Cell Biol. 1999; 19: 6041–6047.
33.
Tanner FC, Boehm M, Akyurek LM, et al. Differential effects of the cyclin-dependent kinase inhibitors p27kip1, p21cip1, and p16ink4 on vascular smooth muscle cell proliferation. Circulation. 2000; 101: 2022–2025.
34. Saunders RN, Metcalfe MS, Nicholson ML. Rapamycin in transplantation: a review of the evidence. Kidney Int. 2001; 59: 3–16.[Medline] [Order article via Infotrieve]
35. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study: the Rapamune US Study Group. Lancet. 2000; 356: 194–202.[Medline] [Order article via Infotrieve]
36.
Sousa JE, Costa MA, Abizaid A, et al. Lack of neotintimal proliferation after implantation of sirolimus-coated stents in human coronary arteries. Circulation. 2001; 103: 192–195.
37.
Albiero R, Nishida T, Adamian M, et al. Edge restenosis after implantation of high activity (32)P radioactive ß-emitting stents. Circulation. 2000; 101: 2454–2457.
38. Sousa JE, Costa MA, Abizaid A, et al. Mid- (4 month) and long-term (1 year) QCA and three dimensional IVUS followup after implantation of sirolimus-coated stent in human coronary arteries. J Am Coll Cardiol. 2001; 37 (suppl A): 8A.Abstract.
39. Feres F, Costa MA, Abazaid A, et al. Comparison between sirolimus-coated and noncoated stent implantation in human coronary arteries. J Am Coll Cardiol. 2001; 37 (suppl A): 47A.Abstract.
40. Yeung AC, Davis SF, Hauptmann PJ. Incidence and progression of transplant coronary artery disease over 1 year: results of a multicenter trial with use of intravascular ultrasound. J Heart Lung Transplant. 1995; 14: S215–S220.[Medline] [Order article via Infotrieve]
41. Meiser B, Billingham M, Morris R. Effects of cyclosporin, FK506, and rapamycin on graft-vessel disease. Lancet. 1991; 338: 1297–1298.[Medline] [Order article via Infotrieve]
42.
Poston RS, Billingham M, Hoyt G, et al. Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model. Circulation. 1999; 100: 67–74.
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J. J. Popma, M. B. Leon, J. W. Moses, D. R. Holmes Jr, N. Cox, M. Fitzpatrick, J. Douglas, C. Lambert, M. Mooney, S. Yakubov, et al. Quantitative Assessment of Angiographic Restenosis After Sirolimus-Eluting Stent Implantation in Native Coronary Arteries Circulation, December 21, 2004; 110(25): 3773 - 3780. [Abstract] [Full Text] [PDF]
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K. Toutouzas, A. Colombo, and C. Stefanadis Inflammation and restenosis after percutaneous coronary interventions Eur. Heart J., October 1, 2004; 25(19): 1679 - 1687. [Abstract] [Full Text] [PDF]
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S. Banai, S.D. Gertz, L. Gavish, M. Chorny, L. S. Perez, G. Lazarovichi, M. Ianculuvich, M. Hoffmann, M. Orlowski, G. Golomb, et al. Tyrphostin AGL-2043 eluting stent reduces neointima formation in porcine coronary arteries Cardiovasc Res, October 1, 2004; 64(1): 165 - 171. [Abstract] [Full Text] [PDF]
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 C. C. Yost, M. M. Denis, S. Lindemann, F. J. Rubner, G. K. Marathe, M. Buerke, T. M. McIntyre, A. S. Weyrich, and G. A. Zimmerman Activated Polymorphonuclear Leukocytes Rapidly Synthesize Retinoic Acid Receptor-{alpha}: A Mechanism for Translational Control of Transcriptional Events J. Exp. Med., September 7, 2004; 200(5): 671 - 680. [Abstract] [Full Text] [PDF]
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 T. Schachner, Y. Zou, A. Oberhuber, A. Tzankov, T. Mairinger, G. Laufer, and J. O. Bonatti Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts Ann. Thorac. Surg., May 1, 2004; 77(5): 1580 - 1585. [Abstract] [Full Text] [PDF]
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E. Schampaert, E. A. Cohen, M. Schluter, F. Reeves, M. Traboulsi, L. M. Title, R. E. Kuntz, J. J. Popma, and the C-SIRIUS Investigators The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS) J. Am. Coll. Cardiol., March 17, 2004; 43(6): 1110 - 1115. [Abstract] [Full Text] [PDF]
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T. Force, K. Kuida, M. Namchuk, K. Parang, and J. M. Kyriakis Inhibitors of Protein Kinase Signaling Pathways: Emerging Therapies for Cardiovascular Disease Circulation, March 16, 2004; 109(10): 1196 - 1205. [Abstract] [Full Text] [PDF]
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P. M. Mourani, P. J. Garl, J. M. Wenzlau, T. C. Carpenter, K. R. Stenmark, and M. C.M. Weiser-Evans Unique, Highly Proliferative Growth Phenotype Expressed by Embryonic and Neointimal Smooth Muscle Cells Is Driven by Constitutive Akt, mTOR, and p70S6K Signaling and Is Actively Repressed by PTEN Circulation, March 16, 2004; 109(10): 1299 - 1306. [Abstract] [Full Text] [PDF]
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J. George, J. Sack, I. Barshack, P. Keren, I. Goldberg, R. Haklai, G. Elad-Sfadia, Y. Kloog, and G. Keren Inhibition of Intimal Thickening in the Rat Carotid Artery Injury Model by a Nontoxic Ras Inhibitor Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 363 - 368. [Abstract] [Full Text]
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D. P. Faxon Bringing Reality to Drug-Eluting Stents Circulation, January 20, 2004; 109(2): 140 - 142. [Full Text] [PDF]
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N. Beohar, J. D. Flaherty, C. J. Davidson, R. C. Maynard, J. D. Robbins, A. P. Shah, J. W. Choi, L. A. MacDonald, J. P. Jorgensen, J. V. Pinto, et al. Antirestenotic Effects of a Locally Delivered Caspase Inhibitor in a Balloon Injury Model Circulation, January 6, 2004; 109(1): 108 - 113. [Abstract] [Full Text] [PDF]
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R. M. Drenan, X. Liu, P. G. Bertram, and X. F. S. Zheng FKBP12-Rapamycin-associated Protein or Mammalian Target of Rapamycin (FRAP/mTOR) Localization in the Endoplasmic Reticulum and the Golgi Apparatus J. Biol. Chem., January 2, 2004; 279(1): 772 - 778. [Abstract] [Full Text] [PDF]
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J. W. Moses, M. B. Leon, J. J. Popma, P. J. Fitzgerald, D. R. Holmes, C. O'Shaughnessy, R. P. Caputo, D. J. Kereiakes, D. O. Williams, P. S. Teirstein, et al. Sirolimus-Eluting Stents versus Standard Stents in Patients with Stenosis in a Native Coronary Artery N. Engl. J. Med., October 2, 2003; 349(14): 1315 - 1323. [Abstract] [Full Text] [PDF]
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E. R. Edelman and H. D. Danenberg Rapamycin for Cardiac Transplant Rejection and Vasculopathy: One Stone, Two Birds? Circulation, July 8, 2003; 108(1): 6 - 8. [Full Text] [PDF]
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D. Mancini, S. Pinney, D. Burkhoff, J. LaManca, S. Itescu, E. Burke, N. Edwards, M. Oz, and A. R. Marks Use of Rapamycin Slows Progression of Cardiac Transplantation Vasculopathy Circulation, July 8, 2003; 108(1): 48 - 53. [Abstract] [Full Text] [PDF]
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L. Lipskaia, M.-L. Pourci, C. Delomenie, L. Combettes, D. Goudouneche, J.-L. Paul, T. Capiod, and A.-M. Lompre Phosphatidylinositol 3-Kinase and Calcium-Activated Transcription Pathways Are Required for VLDL-Induced Smooth Muscle Cell Proliferation Circ. Res., May 30, 2003; 92(10): 1115 - 1122. [Abstract] [Full Text] [PDF]
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J. E. Sousa, P. W. Serruys, and M. A. Costa New Frontiers in Cardiology: Drug-Eluting Stents: Part I Circulation, May 6, 2003; 107(17): 2274 - 2279. [Full Text] [PDF]
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P. S. Brara, M. Moussavian, M. A. Grise, J. P. Reilly, M. Fernandez, R. A. Schatz, and P. S. Teirstein Pilot Trial of Oral Rapamycin for Recalcitrant Restenosis Circulation, April 8, 2003; 107(13): 1722 - 1724. [Abstract] [Full Text] [PDF]
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B. W. Fouty and D. M. Rodman Mevastatin Can Cause G1 Arrest and Induce Apoptosis in Pulmonary Artery Smooth Muscle Cells Through a p27Kip1-Independent Pathway Circ. Res., March 21, 2003; 92(5): 501 - 509. [Abstract] [Full Text] [PDF]
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G. A. Visner, F. Lu, H. Zhou, J. Liu, K. Kazemfar, and A. Agarwal Rapamycin Induces Heme Oxygenase-1 in Human Pulmonary Vascular Cells: Implications in the Antiproliferative Response to Rapamycin Circulation, February 18, 2003; 107(6): 911 - 916. [Abstract] [Full Text] [PDF]
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 J Gunn, A C Morton, C Wales, C M H Newman, D C Crossman, and D C Cumberland Drug eluting stents: maximising benefit and minimising cost Heart, February 1, 2003; 89(2): 127 - 131. [Abstract] [Full Text] [PDF]
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 J. R. Rohde and M. E. Cardenas The Tor Pathway Regulates Gene Expression by Linking Nutrient Sensing to Histone Acetylation Mol. Cell. Biol., January 15, 2003; 23(2): 629 - 635. [Abstract] [Full Text] [PDF]
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 T. Decker, S. Hipp, I. Ringshausen, C. Bogner, M. Oelsner, F. Schneller, and C. Peschel Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin Blood, January 1, 2003; 101(1): 278 - 285. [Abstract] [Full Text] [PDF]
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D. P. Faxon Systemic Drug Therapy for Restenosis: "Deja Vu All Over Again" Circulation, October 29, 2002; 106(18): 2296 - 2298. [Full Text] [PDF]
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E. Regar, P.W. Serruys, C. Bode, C. Holubarsch, J.L. Guermonprez, W. Wijns, A. Bartorelli, C. Constantini, M. Degertekin, K. Tanabe, et al. Angiographic Findings of the Multicenter Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL): Sirolimus-Eluting Stents Inhibit Restenosis Irrespective of the Vessel Size Circulation, October 8, 2002; 106(15): 1949 - 1956. [Abstract] [Full Text] [PDF]
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P. W. Serruys, M. Degertekin, K. Tanabe, A. Abizaid, J. E. Sousa, A. Colombo, G. Guagliumi, W. Wijns, W. K. Lindeboom, J. Ligthart, et al. Intravascular Ultrasound Findings in the Multicenter, Randomized, Double-Blind RAVEL (RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) Trial Circulation, August 13, 2002; 106(7): 798 - 803. [Abstract] [Full Text] [PDF]
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M.-C. Morice, P. W. Serruys, J. E. Sousa, J. Fajadet, E. Ban Hayashi, M. Perin, A. Colombo, G. Schuler, P. Barragan, G. Guagliumi, et al. A Randomized Comparison of a Sirolimus-Eluting Stent with a Standard Stent for Coronary Revascularization N. Engl. J. Med., June 6, 2002; 346(23): 1773 - 1780. [Abstract] [Full Text] [PDF]
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 C. Haller Percutaneous coronary interventions in patients with renal failure: overcoming in-stent restenosis? Nephrol. Dial. Transplant., May 1, 2002; 17(5): 701 - 703. [Full Text] [PDF]
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E. T.H. Yeh Ubiquitin, Proteasome, and Restenosis: A Brave New World for Cardiovascular Research Circulation, January 29, 2002; 105(4): 408 - 410. [Full Text] [PDF]
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H. C. Lowe, L. M. Khachigian, J. Sun, S. O. Marx, H.-J. Chen, A. R. Marks, L. E. Rabbani, and M. Poon Coating Stents With Antirestenotic Drugs: The Blunderbuss or the Magic Bullet? Response Circulation, January 29, 2002; 105 (4): e29 - e29. [Full Text] [PDF]
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 G. Mozes and P. Gloviczki Adjuvant Therapy in Lower Extremity Revascularization: Prevention of Early and Intermediate Failures Perspectives in Vascular Surgery and Endovascular Therapy, January 1, 2002; 15(2): 161 - 180. [Abstract] [PDF]
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