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Updated: Jan 4, 2026
Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse
Anca Remes1, Maximilian Franz2, Franziska Mohr3
1Department of Internal Medicine III, University of Kiel and University Hospital Schleswig-Holstein, Kiel, and German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Germany.
Abstract:
Transplant vasculopathy (TV), characterized by obstructive lesions in affected vessels, represents one of the long-term complications of cardiac transplantation. Activation of the transcription factor activator protein-1 (AP-1) is implicated in smooth muscle cell (SMC) phenotypic switch from contractile to synthetic function, increasing the migration and proliferation rate of these cells. We hypothesize that adeno-associated virus (AAV)-mediated delivery of an RNA hairpin AP-1 decoy oligonucleotide (dON) might effectively ameliorate TV severity in a mouse aortic allograft model. Aortic allografts from DBA/2 mice ex vivo transduced with modified AAV9-SLR carrying a targeting peptide within the capsid surface were transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg BW) was administered daily. AP-1 dONs were intracellularly expressed in the graft tissue as small hairpin RNA proved by fluorescent in situ hybridization. Explantation after 30 days and histomorphometric evaluation revealed that AP-1 dON treatment significantly reduced intima-to-media ratio by 41.5% (p < 0.05) in the grafts. In addition, expression of adhesion molecules, cytokines, as well as numbers of proliferative SMCs, matrix metalloproteinase-9-positive cells, and inflammatory cell infiltration were significantly decreased in treated aortic grafts. Our findings demonstrate the feasibility, efficacy, and specificity of the anti-AP-1 RNA dON approach for the treatment of allograft vasculopathy in an animal model. Moreover, the AAV-based approach in general provides the possibility to achieve a prolonged delivery of nucleic-acids-based therapeutics in to the blood vessel wall.
Insights
This study shows that adeno-associated virus (AAV)-delivered RNA decoy oligonucleotides targeting activator protein-1 (AP-1) effectively reduce transplant vasculopathy severity in a mouse model, offering a potential new therapy.
Area of Science:
- Vascular Biology
- Gene Therapy
- Immunology
Background:
- Transplant vasculopathy (TV) is a major long-term complication after cardiac transplantation, characterized by obstructive vascular lesions.
- Activation of transcription factor activator protein-1 (AP-1) drives smooth muscle cell proliferation and migration, contributing to TV development.
- Current treatments for TV are limited, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the efficacy of adeno-associated virus (AAV)-mediated delivery of an AP-1 decoy oligonucleotide (dON) in ameliorating TV in a mouse aortic allograft model.
- To assess the impact of AP-1 dON treatment on vascular remodeling, inflammation, and smooth muscle cell proliferation within the allograft.
Main Methods:
- AAV9-SLR vectors carrying an AP-1 dON were used to transduce mouse aortic allografts ex vivo.
- Transduced allografts were transplanted into C57BL/6 mice, with daily administration of Cyclosporine A.
- Vascular changes, including intima-to-media ratio, cell proliferation, and inflammatory markers, were evaluated 30 days post-transplantation.
Main Results:
- AP-1 dON treatment significantly reduced the intima-to-media ratio in aortic allografts by 41.5% (p < 0.05).
- A significant decrease was observed in the expression of adhesion molecules, cytokines, proliferative smooth muscle cells, matrix metalloproteinase-9, and inflammatory cell infiltration in treated grafts.
- Intracellular expression of AP-1 dON as small hairpin RNA was confirmed in graft tissues.
Conclusions:
- AAV-mediated delivery of anti-AP-1 RNA dON is a feasible and effective strategy for treating allograft vasculopathy in an experimental model.
- This approach demonstrates specificity in reducing key pathological features of TV, including neointimal hyperplasia and inflammation.
- AAV-based gene therapy offers a promising platform for sustained delivery of nucleic acid therapeutics to blood vessel walls for preventing or treating vascular complications.
