title: Differential effects of modern immunosuppressive agents on the development of intimal hyperplasia.
abstract: 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.
authors.affiliation: 2 Great Chilton Farm Cottages, Chilton Lane, Ferryhill, Co. Durham, DL17 9JY, UK. julian@waller720.fsnet.co.uk
authors.forename: Julian R
authors.initials: JR
authors.lastname: Waller
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Brook
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Bicknell
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nicholson
mesh_terms: 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*
chemical_list: 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