Rapamycin has no effect on fibrosis-associated gene expression or extracellular matrix accumulation when administered to animals with established or early allograft vasculopathy.
BACKGROUND
Most patients with functioning heart transplants have established and progressive chronic allograft vasculopathy, a fibroproliferative process for which there is no effective treatment. Coronary artery disease is characterized by histologic evidence of extracellular matrix accumulation (fibrosis). This study compares the effect of rapamycin administered to rats with established allograft vasculopathy on histologic indices of disease progression, extracellular matrix accumulation (fibrosis), and the expression of genes known to regulate extracellular matrix turnover in this model.


METHODS
Lewis recipients of Fisher 344 rat thoracic to abdominal aorta transplants were administered rapamycin starting at 8, 12, and 16 weeks posttransplant or no treatment. Six grafts in each group were harvested at 24 weeks. Vascular remodeling and collagen accumulation (Sirius red) were measured by computerized histomorphometry of aortic sections. mRNA was extracted from frozen tissue, and the expression of fibrosis-associated genes was studied by means of semiquantitative reverse transcriptase-polymerase chain reaction.


RESULTS
Rapamycin had no effect on the progression of early or established allograft vasculopathy with regard to intimal thickening, remodeling, extracellular matrix accumulation, or profibrotic gene expression, regardless of the time commenced.


CONCLUSIONS
The attenuation of the fibroproliferative response in rodents by rapamycin is not seen if the onset of rapamycin therapy is delayed.
Murphy
Gavin J
GJ
University Department of Surgery, Leicester General Hospital, United Kingdom. gavinmurphy@hotmail.com
Nicholson
Michael L
ML
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation*; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D007249:Inflammation; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology*; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D020123:Sirolimus