Skip to main content
SpringerLink
Log in

Dose-dependent Inhibition of Myointimal Hyperplasia by Orally Administered Rapamycin

  • Papers Presented at the Twenty-eighth Annual Meeting of the Peripheral Vascular Surgery Society
  • Published:
Annals of Vascular Surgery

Abstract

Myointimal hyperplasia (MIH) after vascular intervention is a major problem. Recent reports describing elimination of within-stent restenosis by means of rapamycin-eluting stents prompted us to examine the effect of systemic oral rapamycin on MIH induced by arterial trauma. We studied the effect of oral rapamycin on MIH after rabbit aorta balloon injury. Thirty-five New Zealand white rabbits (2.5-3 kg) had aortic injury and were given either no rapamycin (control), 0.1 (low dose) rapamycin mg/kg/day, or 0.4 mg/kg/day (high dose). Rapamycin was started 1 week before injury and continued for 3 (4 weeks total) or 6 weeks (7 weeks total) post-injury. Sections were analyzed to measure aortic intima/media area ratios (I:M) at either 3 or 6 weeks. At 3 weeks, the I:M (mean ± SD) for controls was 0.53 ± 0.1; for low dose, 0.17 ± 0.13; and for high dose, 0.24 ± 0.07 (p < 0.001 vs. control). At 6 weeks, the I:M for controls was 0.52 ± 0.12; for low dose-4 weeks, 0.29 ± 0.15; low dose-7 weeks, 0.33 ± 0.07; and high dose-4 weeks, 0.47 ± 0.16. At 6 weeks only the difference between the low dose-4 weeks and control I:M ratios was significant (p = 0.018). The results confirm earlier studies showing that systemic rapamycin inhibits MIH after arterial injury when drug therapy is started before injury. Therapy for 3 or 6 weeks after injury yields similar inhibition, indicating that exposure to the drug early in the response to injury is more important than prolonged exposure. We observed a paradoxical relation between dose and degree of MIH inhibition, with the low dose being more effective than the high dose at both time intervals studied. Overall, the results suggest that oral rapamycin therapy might be a useful adjunct to clinical interventions at risk for development of MIH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

References

  1. RE Kuntz DS Baim (2000) ArticleTitlePrevention of coronary restenosis: the evolving evidence base for radiation therapy Circulation 101 2130–2133 Occurrence Handle1:STN:280:DC%2BD3c3mtlKgug%3D%3D

    CAS  Google Scholar 

  2. RS Schwartz (1998) ArticleTitlePathophysiology of restenosis: interaction of thrombosis, hyperplasia, and/or remodeling Am. J. Cardiol. 81 14E–17E Occurrence Handle10.1016/S0002-9149(98)00191-X Occurrence Handle1:STN:280:DyaK1c3htFeisw%3D%3D Occurrence Handle9551589

    Article  CAS  PubMed  Google Scholar 

  3. S Sdringola A Assali HV Anderson et al. (2000) ArticleTitleRestenosis: relationship with thrombosis Curr. Interv. Cardiol. Rep. 2 285–292 Occurrence Handle11096678

    PubMed  Google Scholar 

  4. A Farb G Sangiorgi AJ Carter et al. (1999) ArticleTitlePathology of acute and chronic coronary stenting in humans Circulation 99 44–52

    Google Scholar 

  5. P Grewe T Deneke A Machraoui (2000) ArticleTitleAcute and chronic tissue response to coronary stent implantation: pathologic findings in human specimens J. Am. Coll. Cardiol. 35 157–163 Occurrence Handle10.1016/S0735-1097(99)00486-6 Occurrence Handle1:STN:280:DC%2BD3c7gtVahuw%3D%3D Occurrence Handle10636274

    Article  CAS  PubMed  Google Scholar 

  6. ME Billingham (1992) ArticleTitleHistopathology of graft coronary disease J. Heart Lung Transplant. 3 S38–44

    Google Scholar 

  7. E Minar B Pokrajac T Maca et al. (2000) ArticleTitleEndovascular brachytherapy for prophylaxis of restenosis after femoropopliteal angioplasty: results of a prospective randomized study Circulation 102 2694–2699 Occurrence Handle1:STN:280:DC%2BD3M%2FmtVyntA%3D%3D Occurrence Handle11094034

    CAS  PubMed  Google Scholar 

  8. E Regar PW Serruys (2001) ArticleTitleStent development and local drug delivery Br. Med. Bull. 59 227–48 Occurrence Handle10.1093/bmb/59.1.227 Occurrence Handle1:CAS:528:DC%2BD38XhtVyktrw%3D Occurrence Handle11756213

    Article  CAS  PubMed  Google Scholar 

  9. JE Sousa MA Costa AC Abizaid et al. (2001) ArticleTitleSustained suppression of neointimal proliferation by sirolimus-eluting stents: one year angiographic and intravascular ultrasound follow-up Circulation 104 2007–2017 Occurrence Handle1:STN:280:DC%2BD3Mrms12ktQ%3D%3D Occurrence Handle11673337

    CAS  PubMed  Google Scholar 

  10. RE Morris (1992) ArticleTitleRapamycins: antifungal, antitumor, antiproliferative, and immunosuppressive macrolides Transplant. Rev. 6 39–87

    Google Scholar 

  11. PA Nelson JA Lippke MA Murcko et al. (1991) ArticleTitlecDNA coding murine FK506-binding protein (FKBP): nucleotide and deduced amino acid sequence Gene 109 255–258 Occurrence Handle10.1016/0378-1119(91)90617-K Occurrence Handle1:CAS:528:DyaK3sXhs1entbw%3D Occurrence Handle1722474

    Article  CAS  PubMed  Google Scholar 

  12. BA Hendrickson W Zhang RJ Craig et al. (1993) ArticleTitleStructural organization of the genes encoding human and murine FK506-binding protein (FKBP) 13 and comparision to FKBP1 Gene 134 271–275 Occurrence Handle10.1016/0378-1119(93)90106-D Occurrence Handle1:CAS:528:DyaK2cXkslWksg%3D%3D Occurrence Handle7505249

    Article  CAS  PubMed  Google Scholar 

  13. RT Abraham (1996) ArticleTitlePhosphatidylinositol-3-kinase related kinases Curr. Opin. Immunol. 8 212–418 Occurrence Handle10.1016/S0952-7915(96)80132-4

    Article  Google Scholar 

  14. KL Napoli PJ Taylor (2001) ArticleTitleFrom beach to bedside: history of the development of sirolimus Ther. Drug Monit. 23 559–586

    Google Scholar 

  15. SO Marx T Jayaraman LO Go et al. (1995) ArticleTitleRapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells Circ. Res. 76 412–417 Occurrence Handle1:CAS:528:DyaK2MXkt1Wku7o%3D Occurrence Handle7532117

    CAS  PubMed  Google Scholar 

  16. I Reynidottir K Polyak A Iavarone et al. (1995) ArticleTitleKip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta Genes Dev. 9 1831–1845 Occurrence Handle7649471

    PubMed  Google Scholar 

  17. J Nourse E Firpo WM Flanagan et al. (1994) ArticleTitleInterleukin-2 mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin Nature 372 570–573 Occurrence Handle1:CAS:528:DyaK2MXisFKktb4%3D Occurrence Handle7990932

    CAS  PubMed  Google Scholar 

  18. Y Akselband MW Harding PA Nelson (1991) ArticleTitleRapamycin inhibits spontaneous and fibroblast growth factor beta-stimulated proliferation of endothelial cells and fibroblasts Transplant. Proc. 23 2833–6 Occurrence Handle1:CAS:528:DyaK38XnsFyqsw%3D%3D

    CAS  Google Scholar 

  19. M Poon SO Marx R Gallo et al. (1996) ArticleTitleRapamycin inhibits vascular smooth muscle cell migration J. Clin. Invest. 98 2277–2283 Occurrence Handle1:CAS:528:DyaK28XntVOhsLk%3D Occurrence Handle8941644

    CAS  PubMed  Google Scholar 

  20. CR Gregory P Huie ME Billingham et al. (1993) ArticleTitleRapamycin inhibits arterial intimal thickening caused buy both alloimmune and mechanical injury. Its effect on cellular, growth factor, and cytokine response in injured vessels Transplantation 55 149–1418

    Google Scholar 

  21. RW Yatscoff P Wang K Chan et al. (1995) ArticleTitleRapamycin: distribution, pharmacokinetics, and therapeutic range investigations Ther. Drug. Monit. 17 666–671

    Google Scholar 

  22. M Sattler FP Guengerich CH Yun et al. (1992) ArticleTitleCytochrome P-450 3A enzyme are responsible for biotransformation of FK506 and rapamycin in man and rat Drug Metab. Dispos. 20 753–761

    Google Scholar 

  23. A Crowe A Bruelisauer L Duerr et al. (1999) ArticleTitleAbsorption and intestinal metabolism of SDZ-RAD and rapamycin in rats Drug Metab. Dispos. 27 627–632

    Google Scholar 

  24. RW Yatscoff P Wang K Chan D Hicks J Zimmerman (1995) ArticleTitleRapamycin: distribution, pharmacokinetics, and therapeutic range investigations Ther. Drug Monit. 17 666–671

    Google Scholar 

  25. PS Almond A Moss R Nakhleh et al. (1993) ArticleTitleRapamycin: immunosuppression, hyporesponsiveness and side effects in a porcine renal allograft model Transplantation 56 275–281 Occurrence Handle1:CAS:528:DyaK2cXhsFehtL0%3D Occurrence Handle8356580

    CAS  PubMed  Google Scholar 

  26. VC Dias KL Madsen RW Yatscoff et al. (1994) ArticleTitleOrally administered immunosuppressants modify intestinal uptake of nutrients in rabbits Transplantation 15 1241–1246

    Google Scholar 

  27. T Nagae K Aizawa N Uchimura et al. (2001) ArticleTitleEndovascular photodynamic therapy using mono-L-aspartyl-chlorin e6 to inhibit intimal hyperplasia in balloon-injured rabbit arteries Lasers Surg. Med. 28 381–388 Occurrence Handle10.1002/lsm.1066 Occurrence Handle1:STN:280:DC%2BD3M3kt1aguw%3D%3D

    Article  CAS  Google Scholar 

  28. RD Sayers L Jones K Varty et al. (1993) ArticleTitleThe histopathology of infrainguinal vein graft stenoses Eur. J. Vasc. Surg. 7 16–20 Occurrence Handle1:STN:280:ByyB3c3ivV0%3D

    CAS  Google Scholar 

  29. AW Barolet S Babaei R Robinson et al. (2001) ArticleTitleAdministration of exogenous endothelin-1 following vascular balloon injury: early and late effects on intimal hyperplasia Cardiovasc. Res. 52 468–476 Occurrence Handle10.1016/S0008-6363(01)00431-X Occurrence Handle1:CAS:528:DC%2BD3MXovVChtrc%3D Occurrence Handle11738064

    Article  CAS  PubMed  Google Scholar 

  30. SE Burke NL Lubbers YW Chen et al. (1999) ArticleTitleNeointimal formation after balloon-induced vascular injury in Yucatan minipigs is reduced by oral rapamycin J. Cardiovasc. Pharmacol. 33 829–835 Occurrence Handle10.1097/00005344-199906000-00001 Occurrence Handle1:CAS:528:DyaK1MXjsVyqs7s%3D Occurrence Handle10367584

    Article  CAS  PubMed  Google Scholar 

  31. TS Ikonen JF Gummert M Hayase et al. (2000) ArticleTitleSirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates Transplantation 70 969–975

    Google Scholar 

  32. WC Goggins RA Fisher DS Cohen et al. (1996) ArticleTitleEffect of single-dose rapamycin-based immunosuppression on the development of cardiac allograft vasculopathy J. Heart Lung Transplant. 15 790–795 Occurrence Handle1:STN:280:ByiD3szgtFc%3D Occurrence Handle8878761

    CAS  PubMed  Google Scholar 

  33. CR Gregory X Huang RE Pratt et al. (1994) ArticleTitleTreatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement Transplantation 59 655–661

    Google Scholar 

  34. A Farb M John E Acampado et al. (2002) ArticleTitleOral Everolimus inhibits in-stent neointimal growth Circulation 106 2379–2384 Occurrence Handle10.1161/01.CIR.0000033973.06059.04 Occurrence Handle1:CAS:528:DC%2BD38XotV2iurk%3D

    Article  CAS  Google Scholar 

  35. T Suzuki G Kopia S Hayashi et al. (2001) ArticleTitleStent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model Circulation 104 1183–1193

    Google Scholar 

  36. BD Klugherz G Llanos W Lieuallen et al. (2002) ArticleTitleTwenty-eight-day efficacy and pharmacokinetics of the sirolimus-eluting stent Coron. Artery Dis. 13 183–188 Occurrence Handle10.1097/00019501-200205000-00008

    Article  Google Scholar 

  37. BJ Rensing J Vos PC Smits et al. (2001) ArticleTitleCoronary restenosis elimination with a sirolimus eluting stent Eur. Heart J. 22 2125–2130 Occurrence Handle10.1053/euhj.2001.2892 Occurrence Handle1:STN:280:DC%2BD3MnjvFSguw%3D%3D Occurrence Handle11686669

    Article  CAS  PubMed  Google Scholar 

  38. DC Wright HS Deol BE Tuch (1999) ArticleTitleA comparision of the sensitivity of pig and human peripheral blood mononuclear cells to the anti-proliferative effects of traditional and newer immunosuppressive agents Transplant. Immunol. 7 141–147 Occurrence Handle10.1016/S0966-3274(99)80033-1 Occurrence Handle1:CAS:528:DC%2BD3cXhvVyqsQ%3D%3D

    Article  CAS  Google Scholar 

  39. GM Ferron WJ Jusko (1998) ArticleTitleSpecies differences in sirolimus stability in humans, rabbits, and rats Drug Metab. Dispos. 26 83–84

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, University of California Irvine Medical Center, Orange, CA, USA

    Norio Uchimura MD, PhD, Ganesha B. Perera MD, Roy M. Fujitani MD, Samuel E. Wilson MD & Ian L. Gordon MD, PhD

  2. Department of Surgery, Tokyo Medical University, Tokyo, Japan

    Norio Uchimura MD, PhD & Shin Ishimaru MD, PhD

  3. Department of Cardiology, University of California Los Angeles, Los Angeles, CA, USA

    Jonathan M. Tobis MD

Authors
  1. Norio Uchimura MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ganesha B. Perera MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roy M. Fujitani MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan M. Tobis MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shin Ishimaru MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Samuel E. Wilson MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ian L. Gordon MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ian L. Gordon MD, PhD.

About this article

Cite this article

Uchimura, N., Perera, G.B., Fujitani, R.M. et al. Dose-dependent Inhibition of Myointimal Hyperplasia by Orally Administered Rapamycin. Ann Vasc Surg 18, 172–177 (2004). https://doi.org/10.1007/s10016-004-0010-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10016-004-0010-0

Keywords

Search

Navigation