AAV-mediated TIMP-1 overexpression in aortic tissue reduces the severity of allograft vasculopathy in mice

• Verfasst von: Remes, Anca [VerfasserIn]
• Verfasst von: Franz, Maximilian [VerfasserIn]
• Verfasst von: Zaradzki, Marcin [VerfasserIn]
• Verfasst von: Borowski, Christopher [VerfasserIn]
• Verfasst von: Frey, Norbert [VerfasserIn]
• Verfasst von: Karck, Matthias [VerfasserIn]
• Verfasst von: Kallenbach, Klaus [VerfasserIn]
• Verfasst von: Müller, Oliver J. [VerfasserIn]
• Verfasst von: Wagner, Andreas H. [VerfasserIn]
• Verfasst von: Arif, Rawa [VerfasserIn]
• Titel: AAV-mediated TIMP-1 overexpression in aortic tissue reduces the severity of allograft vasculopathy in mice
• Verf.angabe: Anca Remes, Maximilian Franz, Marcin Zaradzki, Christopher Borowski, Norbert Frey, Matthias Karck, Klaus Kallenbach, Oliver J. Müller, Andreas H. Wagner, and Rawa Arif
• E-Jahr: 2020
• Jahr: 30 January 2020
• Umfang: 10 S.
• Fussnoten: Gesehen am 23.04.2020
• Titel Quelle: Enthalten in: The journal of heart and lung transplantation
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1999
• Jahr Quelle: 2020
• Band/Heft Quelle: 39(2020), 4, Seite 389-398
• ISSN Quelle: 1557-3117
• DOI: doi:10.1016/j.healun.2020.01.1338
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: adeno-associated virus
• Sach-SW: allograft vasculopathy
• Sach-SW: gene therapy
• Sach-SW: matrix metalloproteinases
• Sach-SW: tissue inhibitor of metalloproteinases
• K10plus-PPN: 1695834267

Abstract

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.