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SDF-1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy

Chronic rejection remains a major obstacle in transplant medicine. Recent studies suggest a crucial role of the chemokine SDF-1 on neointima formation after injury. Here, we investigate the potential therapeutic effect of inhibiting the SDF-1/CXCR4/CXCR7 axis with an anti-SDF-1 Spiegelmer (NOX-A12)...

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Main Authors: Thomas, Michael Nikolaus (Author) , Kalnins, Aivars (Author) , Andrassy, Martin (Author) , Wagner, Anne (Author) , Klussmann, Sven (Author) , Rentsch, Markus (Author) , Habicht, Antje (Author) , Pratschke, Sebastian (Author) , Stangl, Manfred Johannes (Author) , Bazhin, Alexandr V. (Author) , Meiser, Bruno (Author) , Fischereder, Michael (Author) , Werner, Jens (Author) , Guba, Markus (Author) , Andrassy, Joachim (Author)
Format: Article (Journal)
Language:English
Published: 1 September 2015
In: Transplant international
Year: 2015, Volume: 28, Issue: 12, Pages: 1426-1435
ISSN:1432-2277
DOI:10.1111/tri.12651
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1111/tri.12651
Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1111/tri.12651
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Author Notes:Michael N. Thomas, Aivars Kalnins, Martin Andrassy, Anne Wagner, Sven Klussmann, Markus Rentsch, Antje Habicht, Sebastian Pratschke, Manfred Stangl, Alexandr V. Bazhin, Bruno Meiser, Michael Fischereder, Jens Werner, Markus Guba, Joachim Andrassy
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Summary:Chronic rejection remains a major obstacle in transplant medicine. Recent studies suggest a crucial role of the chemokine SDF-1 on neointima formation after injury. Here, we investigate the potential therapeutic effect of inhibiting the SDF-1/CXCR4/CXCR7 axis with an anti-SDF-1 Spiegelmer (NOX-A12) on the development of chronic allograft vasculopathy. Heterotopic heart transplants from H-2bm12 to B6 mice and aortic transplants from Balb/c to B6 were performed. Mice were treated with NOX-A12. Control animals received a nonfunctional Spiegelmer (revNOX-A12). Samples were retrieved at different time points and analysed by histology, RT-PCR and proliferation assay. Blockade of SDF-1 caused a significant decrease in neointima formation as measured by intima/media ratio (1.0 ± 0.1 vs. 1.8 ± 0.1, P < 0.001 AoTx; 0.35 ± 0.05 vs. 1.13 ± 0.27, P < 0.05 HTx). In vitro treatment of primary vascular smooth muscle cells with NOX-A12 showed a significant reduction in proliferation (0.42 ± 0.04 vs. 0.24 ± 0.03, P < 0.05). TGF-β, TNF-α and IL-6 levels were significantly reduced under SDF-1 inhibition (3.42 ± 0.37 vs. 1.67 ± 0.33, P < 0.05; 2.18 ± 0.37 vs. 1.0 ± 0.39, P < 0.05; 2.18 ± 0.26 vs. 1.6 ± 0.1, P < 0.05). SDF-1/CXCR4/CXCR7 plays a critical role in the development of chronic allograft vasculopathy (CAV). Therefore, pharmacological inhibition of SDF-1 with NOX-A12 may represent a therapeutic option to ameliorate chronic rejection changes.
Item Description:Gesehen am 01.07.2020
Physical Description:Online Resource
ISSN:1432-2277
DOI:10.1111/tri.12651

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