Rapamycin inhibits vascular remodeling in an experimental model of allograft vasculopathy and attenuates associated changes in fibrosis-associated gene expression.
BACKGROUND
Rapamycin inhibits extracellular matrix (ECM) accumulation (fibrosis) and vascular remodeling in experimental models of chronic allograft dysfunction (CAD) by poorly understood mechanisms. The aim of this study was to assess the effect of rapamycin on the expression of fibrosis-associated genes and correlate this with observed changes in ECM remodeling in an experimental of model allograft vasculopathy.


METHODS
Vascular remodeling and ECM accumulation (picrosirius red) were measured by computerized histomorphometry of F344-to-Lewis rat aortic allograft sections harvested at serial timepoints. Expression of fibrosis associated genes was studied by means of semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
Rapamycin (0.5 mg/kg/day) inhibited intimal hyperplasia, medial ECM accumulation and expansive vascular remodeling (increasing vessel circumference) in rat aortic allografts. This was associated with attenuation of the graft inflammatory infiltrate and a reduction in intragraft gelatinase, collagen III and tissue inhibitor of metalloproteinase 1 (TIMP 1) mRNA levels. At a lower dosage (0.25 mg/kg/day), rapamycin inhibited intimal hyperplasia and medial ECM accumulation, but there was a lesser effect on vascular remodeling. Lower dose allografts were also seen to have a more severe inflammatory infiltrate and larger amounts of intragraft matrix metalloproteinase 9 (MMP 9) mRNA than those treated with the higher dose.


CONCLUSIONS
These data suggest that, in addition to the tissue response to injury, the alloimmune injury itself may contribute directly to the vascular remodeling that occurs in allograft vasculopathy. Rapamycin at higher but not lower doses inhibited both of these pathologic processes.
University Department of Surgery, Leicester General Hospital, Leicester, UK. gavinmurphy@hotmail.com
G J
GJ
Murphy
G R
GR
Bicknell
M L
ML
Nicholson
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000473:pathology*; D015870:Gene Expression; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D023421:Models, Animal; D016377:Organ Transplantation / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000494:pharmacology*; D014652:Vascular Diseases / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology
D007166:Immunosuppressive Agents; D020123:Sirolimus