AAV-mediated TIMP-1 overexpression in aortic tissue reduces the severity of allograft vasculopathy in mice
Background: Allograft vasculopathy (AV) is the primary limiting factor for long-term graft survival. An increased activity of matrix metalloproteinases (MMPs) contributes to neointima formation in AV and represents a potential therapeutic target. Adeno-associated virus (AAV)-mediated gene therapy co...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
30 January 2020
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| In: |
The journal of heart and lung transplantation
Year: 2020, Volume: 39, Issue: 4, Pages: 389-398 |
| ISSN: | 1557-3117 |
| DOI: | 10.1016/j.healun.2020.01.1338 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.healun.2020.01.1338 Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S1053249820313565 
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| Author Notes: | Anca Remes, Maximilian Franz, Marcin Zaradzki, Christopher Borowski, Norbert Frey, Matthias Karck, Klaus Kallenbach, Oliver J. Müller, Andreas H. Wagner, and Rawa Arif |
| Summary: | Background: Allograft vasculopathy (AV) is the primary limiting factor for long-term graft survival. An increased activity of matrix metalloproteinases (MMPs) contributes to neointima formation in AV and represents a potential therapeutic target. Adeno-associated virus (AAV)-mediated gene therapy comprises a potentially benign vector model for the long-term expression of MMP antagonists. - Methods: Aortic allografts from DBA/2 mice were incubated with control buffer, AAV-enhanced green fluorescence protein (EGFP), or tissue inhibitor of metalloproteinases 1 (TIMP-1)-loaded AAV (AAV-TIMP-1) and transplanted into the infrarenal aorta of C57BL/6 mice. Cyclosporine A (10 mg/kg body weight) was administered daily. Explantation as well as histomorphometric and immunohistochemical evaluation was performed after 30 days. Matrix metalloproteinase (MMP) activity was visualized by gelatin in situ zymography. - Results: Intima-to-media area ratio and neointima formation were significantly reduced in the AAV-TIMP-1 treatment group compared with those in the control group (by 40%; p < 0.001) and the AAV-EGFP group (by 38.2%; p < 0.001). TIMP-1 overexpression positively affected several pathomechanisms for the development of AV both in vitro and in vivo as compared to that in the control groups: endothelium integrity was preserved as shown by zona occludens 1 and occludin staining; MMP9 expression and activity were significantly reduced (p=0.01); and smooth muscle cell migration was significantly reduced as smooth muscle actin positive cells predominantly remained in the aortic media in the treatment group (p=0.001). Moreover, macrophage infiltration was markedly reduced by 49% in the AAV-TIMP-1 group (p < 0.001). - Conclusion: Immediate post-harvesting allograft incubation with AAV-TIMP-1 reduces neointima formation and macrophage infiltration, constituting a possible adjunct therapeutic strategy to preserve graft function after transplantation. |
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| Item Description: | Gesehen am 23.04.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1557-3117 |
| DOI: | 10.1016/j.healun.2020.01.1338 |