Differential effects of modern immunosuppressive agents on the development of intimal hyperplasia.
Modern immunosuppressive agents such as tacrolimus and rapamycin are claimed to be associated with a reduction in vascular narrowing, a central feature of chronic rejection. This study assesses the effect of cyclosporine, tacrolimus and rapamycin on the development of intimal thickening, fibrosis-associated genes and deposition of extracellular matrix (ECM) proteins in a model of intimal hyperplasia. Male Sprague-Dawley rats received either no treatment or 5 mg/kg cyclosporine, 0.1 mg/kg tacrolimus or 0.05 mg/kg rapamycin. Animals underwent left common carotid balloon angioplasty, and intima medial ratios, pro-fibrotic gene expression and ECM accumulation were calculated at 14 and 28 days. Cyclosporine was associated with increased intimal thickening compared to controls ( P < 0.004). Tacrolimus had no effect on intimal thickening, whilst rapamycin significantly inhibited intimal thickening at both 14 and 28 days ( P < 0.004 and P < 0.026, respectively). All groups significantly inhibited matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, transforming growth factor (TGF)-beta and collagen III expression at 14 days ( P < 0.001), but increased ECM deposition. However, rapamycin marginally reduced ECM deposition compared to cyclosporine ( P < 0.06). Treatment with cyclosporine was associated with worsening of vascular narrowing, whilst rapamycin showed a beneficial reduction in intimal thickening. Treatment with all immunosuppressive agents resulted in increased ECM deposition. Rapamycin may halt the progression of vascular narrowing compared to both cyclosporine and tacrolimus.
Waller
Julian R
JR
2 Great Chilton Farm Cottages, Chilton Lane, Ferryhill, Co. Durham, DL17 9JY, UK. julian@waller720.fsnet.co.uk
Brook
Nicholas R
NR
Bicknell
Gareth R
GR
Nicholson
Michael L
ML
D000800:Angioplasty, Balloon; D000818:Animals; D017536:Carotid Artery, Common; D024061:Collagen Type III / Q000037:antagonists & inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D006965:Hyperplasia; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*
D024061:Collagen Type III; D016326:Extracellular Matrix Proteins; D007166:Immunosuppressive Agents; D061965:Matrix Metalloproteinase Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus