Rapamycin has no effect on fibrosis-associated gene expression or extracellular matrix accumulation when administered to animals with established or early allograft vasculopathy
Related Experiment Video
Updated: Aug 29, 2026
Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin
Published on: September 12, 2019
Gavin J Murphy1, Michael L Nicholson
1University Department of Surgery, Leicester General Hospital, United Kingdom. gavinmurphy@hotmail.com
Insights
Rapamycin did not prevent chronic allograft vasculopathy progression in heart transplant rats, even when initiated later. Delayed rapamycin therapy showed no benefit in reducing fibrosis or vascular remodeling in this model.
Area of Science:
- Cardiology
- Immunology
- Transplantation
Background:
- Chronic allograft vasculopathy (CAV) is a progressive complication after heart transplantation.
- CAV involves significant fibrosis and extracellular matrix accumulation, lacking effective treatments.
- Current research explores therapeutic interventions for established CAV.
Purpose of the Study:
- To evaluate the efficacy of rapamycin in established chronic allograft vasculopathy in a rat model.
- To assess rapamycin's impact on histological indices, fibrosis, and gene expression related to extracellular matrix turnover.
- To determine if the timing of rapamycin initiation affects its therapeutic potential in CAV.
Main Methods:
- Lewis rats received Fisher 344 aorta transplants and were treated with rapamycin at 8, 12, or 16 weeks post-transplant, or received no treatment.
- Grafts were harvested at 24 weeks for histomorphometry to measure vascular remodeling and collagen accumulation.
- Gene expression analysis of fibrosis-associated genes was performed using reverse transcriptase-polymerase chain reaction.
Main Results:
- Rapamycin treatment did not alter intimal thickening or vascular remodeling in established CAV.
- No significant differences in extracellular matrix accumulation or profibrotic gene expression were observed.
- The timing of rapamycin administration did not influence its lack of efficacy in established disease.
Conclusions:
- Delayed initiation of rapamycin therapy does not attenuate the fibroproliferative response in established CAV.
- Rapamycin is ineffective in treating established chronic allograft vasculopathy in this rodent model.
- The findings suggest rapamycin may not be a viable treatment option for established CAV when initiated late.
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.
Conclusion:
The attenuation of the fibroproliferative response in rodents by rapamycin is not seen if the onset of rapamycin therapy is delayed.
