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


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 (> or =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 70-kDa S6 kinase (p70S6k). FK506 (1-1000 ng/ml) did not affect cSMC proliferation alone, although a > or =250-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).


CONCLUSIONS
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.
Hafizi
Sassan
S
Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine at the Heart Science Centre, Harefield Hospital, Middlesex, United Kingdom. sassan.hafizi@klkemi.mas.lu.se
Mordi
Vanessa N
VN
Andersson
Klara M
KM
Chester
Adrian H
AH
Yacoub
Magdi H
MH
D019898:Autocrine Communication / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D016559:Tacrolimus / Q000378:metabolism / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology
D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus