Mycophenolate mofetil inhibits intimal hyperplasia and attenuates the expression of genes favouring smooth muscle cell proliferation and migration.
OBJECTIVE
Intimal hyperplasia remains the leading cause of late graft failure following heart transplantation. The immunosuppressive drug mycophenolate mofetil has been shown to inhibit the development of intimal hyperplasia. This study aimed to assess the efficacy of a combination of mycophenolate mofetil, calcineurin inhibition, and sirolimus on the development of intimal hyperplasia.


METHODS
Male Sprague-Dawley rats received mycophenolate mofetil (30 mg/kg per day) and either tacrolimus (0.1 mg/kg per day), cyclosporine (5 mg/kg per day), or sirolimus (0.05 mg/kg per day) and were compared to an untreated control group. All animals underwent left common carotid artery balloon angioplasty. Morphometric analysis was performed on representative transverse sections, and intima medial ratios calculated at 2 weeks. Profibrotic gene expression was assessed with competitive RT-PCR at 2 weeks for metalloproteinase-2, metalloproteinase-9, TIMP-1, collagen III, and TGF-beta. Sections were stained with sirius red, and extracellular matrix deposition was quantified.


RESULTS
Mycophenolate mofetil in combination with rapamycin was associated with the greatest reduction in intimal thickening (intima medial ratio 0.79; range 0.45-0.86), compared to its combination with either cyclosporine (1.41; range 1.06-1.68, P < .02) or tacrolimus (0.93; range 0.81-1.37, P < .05) and controls (1.47; range 1.02-2.04, P < .005). Mycophenolate mofetil and rapamycin significantly inhibited all profibrotic genes studied compared to controls (P < .01) but there were no differences between tacrolimus and cyclosporine. Mycophenolate mofetil and sirolimus significantly attenuated extracellular matrix deposition compared to tacrolimus and cyclosporin (P < .023).


CONCLUSIONS
The benefits of mycophenolate mofetil in combination with sirolimus are preferential over those with cyclosporine or tacrolimus. Randomised trials are warranted to assess if mycophenolate mofetil should be an alternative agent to calcineurin-inhibitors when used in combination with sirolimus.
Waller
J R
JR
Royal College of Surgeons of England Surgical Research Fellow, Division of Transplant Surgery, Leicester General Hospital, Leicester, UK. julian@waller720.fsnet.co.uk
Brook
N R
NR
Bicknell
G R
GR
Murphy
G J
GJ
Nicholson
M L
ML
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D017536:Carotid Artery, Common; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006965:Hyperplasia / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus