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Differential effects of rapamycin, cyclosporine A, and FK506 on human coronary artery smooth muscle cell proliferation and signalling

Hafizi, Sassan LU ; Mordi, VN; Andersson, KM; Chester, AH and Yacoub, MH (2004) In Vascular Pharmacology2002-01-01+01:00 41(4-5). p.167-176
Abstract
Background: Immunosuppressive agents are at the forefront of preventing organ rejection after transplantation. However, their effects on vascular smooth muscle cell-mediated intimal hyperplasia that occurs in post-transplant coronary artery disease are less well known. Methods and results: We investigated the in vitro effects of three immunosuppressive agents cyclosporine A (CsA), FK506 (tacrolimus), and rapamycin (sirolimus, Rapa) on cultured human coronary artery smooth muscle cells (cSMC). CsA inhibited both platelet-derived growth factor (PDGF)-stimulated DNA synthesis and serum-induced proliferation at high concentrations (greater than or equal to 1000 ng/ ml). The growth-inhibitory effect of CsA was not altered by anti-TGF-beta... (More)
Background: Immunosuppressive agents are at the forefront of preventing organ rejection after transplantation. However, their effects on vascular smooth muscle cell-mediated intimal hyperplasia that occurs in post-transplant coronary artery disease are less well known. Methods and results: We investigated the in vitro effects of three immunosuppressive agents cyclosporine A (CsA), FK506 (tacrolimus), and rapamycin (sirolimus, Rapa) on cultured human coronary artery smooth muscle cells (cSMC). CsA inhibited both platelet-derived growth factor (PDGF)-stimulated DNA synthesis and serum-induced proliferation at high concentrations (greater than or equal to 1000 ng/ ml). The growth-inhibitory effect of CsA was not altered by anti-TGF-beta neutralising antibodies nor was autocrine TGF-beta release detected in CsA-treated culture medium. At inhibitory doses, CsA inhibited ERK kinase activation by PDGF, although cytotoxicity was also apparent. Most notably, CsA visibly prevented PDGF-induced altered cell morphology. Rapa was a highly potent and effective inhibitor of cSMC proliferation (reduction in DNA synthesis by >50% from 0.01 ng/ml), acting through inhibition of 70kDa S6 kinase (p70(S6k)). FK506 (1-1000 ng/ml) did not affect cSMC proliferation alone, although a greater than or equal to250-fold excess of FK506 over Rapa completely reversed the inhibitory effect of Rapa, confirming that these two agents share a common intracellular receptor, the FK506-binding protein (FKBP). Conclusion: Rapa is a powerful inhibitor of cSMC proliferation, while CsA slighly inhibits cSMC proliferation, although only at higher concentrations that may be toxic. These results indicate that therapeutic immunosuppression with Rapa may be additionally useful in prevention or delay of posttransplant coronary artery disease. (C) 2004 Elsevier Inc. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
proliferation, human, coronary, immunosuppressants, vascular smooth muscle cells
in
Vascular Pharmacology2002-01-01+01:00
volume
41
issue
4-5
pages
167 - 176
publisher
Elsevier
external identifiers
  • wos:000226268800007
  • scopus:10644288652
ISSN
1537-1891
DOI
10.1016/j.vph.2004.10.002
language
English
LU publication?
yes
id
3f22ce43-f6ca-44ab-976b-54cdd381cf4f (old id 912259)
date added to LUP
2008-01-10 15:59:21
date last changed
2017-01-01 05:16:28
@article{3f22ce43-f6ca-44ab-976b-54cdd381cf4f,
  abstract     = {Background: Immunosuppressive agents are at the forefront of preventing organ rejection after transplantation. However, their effects on vascular smooth muscle cell-mediated intimal hyperplasia that occurs in post-transplant coronary artery disease are less well known. Methods and results: We investigated the in vitro effects of three immunosuppressive agents cyclosporine A (CsA), FK506 (tacrolimus), and rapamycin (sirolimus, Rapa) on cultured human coronary artery smooth muscle cells (cSMC). CsA inhibited both platelet-derived growth factor (PDGF)-stimulated DNA synthesis and serum-induced proliferation at high concentrations (greater than or equal to 1000 ng/ ml). The growth-inhibitory effect of CsA was not altered by anti-TGF-beta neutralising antibodies nor was autocrine TGF-beta release detected in CsA-treated culture medium. At inhibitory doses, CsA inhibited ERK kinase activation by PDGF, although cytotoxicity was also apparent. Most notably, CsA visibly prevented PDGF-induced altered cell morphology. Rapa was a highly potent and effective inhibitor of cSMC proliferation (reduction in DNA synthesis by >50% from 0.01 ng/ml), acting through inhibition of 70kDa S6 kinase (p70(S6k)). FK506 (1-1000 ng/ml) did not affect cSMC proliferation alone, although a greater than or equal to250-fold excess of FK506 over Rapa completely reversed the inhibitory effect of Rapa, confirming that these two agents share a common intracellular receptor, the FK506-binding protein (FKBP). Conclusion: Rapa is a powerful inhibitor of cSMC proliferation, while CsA slighly inhibits cSMC proliferation, although only at higher concentrations that may be toxic. These results indicate that therapeutic immunosuppression with Rapa may be additionally useful in prevention or delay of posttransplant coronary artery disease. (C) 2004 Elsevier Inc. All rights reserved.},
  author       = {Hafizi, Sassan and Mordi, VN and Andersson, KM and Chester, AH and Yacoub, MH},
  issn         = {1537-1891},
  keyword      = {proliferation,human,coronary,immunosuppressants,vascular smooth muscle cells},
  language     = {eng},
  number       = {4-5},
  pages        = {167--176},
  publisher    = {Elsevier},
  series       = {Vascular Pharmacology2002-01-01+01:00},
  title        = {Differential effects of rapamycin, cyclosporine A, and FK506 on human coronary artery smooth muscle cell proliferation and signalling},
  url          = {http://dx.doi.org/10.1016/j.vph.2004.10.002},
  volume       = {41},
  year         = {2004},
}