Open AccessSDF ‐1/ CXCR 4/ CXCR 7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy
Author(s) -
Thomas Michael N.,
Kalnins Aivars,
Andrassy Martin,
Wagner Anne,
Klussmann Sven,
Rentsch Markus,
Habicht Antje,
Pratschke Sebastian,
Stangl Manfred,
Bazhin Alexandr V.,
Meiser Bruno,
Fischereder Michael,
Werner Jens,
Guba Markus,
Andrassy Joachim
Publication year - 2015
Publication title -
transplant international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.998
H-Index - 82
eISSN - 1432-2277
pISSN - 0934-0874
DOI - 10.1111/tri.12651
Subject(s) - neointima , medicine , cxcr4 , vascular smooth muscle , blockade , chemokine , transplantation , immunology , pathology , pharmacology , inflammation , receptor , smooth muscle , restenosis , stent
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/ CXCR 4/ CXCR 7 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 (rev NOX ‐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 HT x). 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/ CXCR 4/ CXCR 7 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.