SDF‐1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy
SDF‐1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy
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DOI：
10.1111/tri.12651
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发表时间：
2015-12
影响因子：
3.1
通讯作者：
M. Thomas;A. Kalnins;M. Andrassy;A. Wagner;S. Klußmann;M. Rentsch;A. Habicht;S. Pratschke;M. Stangl;A. Bazhin;B. Meiser;M. Fischereder;J. Werner;M. Guba;J. Andrassy
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文献类型：
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作者：
M. Thomas;A. Kalnins;M. Andrassy;A. Wagner;S. Klußmann;M. Rentsch;A. Habicht;S. Pratschke;M. Stangl;A. Bazhin;B. Meiser;M. Fischereder;J. Werner;M. Guba;J. Andrassy
慢性排斥反应仍然是移植医学的主要障碍。最近的研究表明，趋化因子SDF-1在损伤后新生内膜形成中起着关键作用。在这里，我们研究了用抗SDF-1 Spiegelmer（NOX-A12）抑制SDF-1/CXCR 4/CXCR 7轴对慢性同种异体移植物血管病变发展的潜在治疗作用。进行了从H-2bm 12到B6小鼠的异位心脏移植和从Balb/c到B6的主动脉移植。用NOX-A12处理小鼠。对照动物接受非功能性Spiegelmer（revNOX‐A12）。在不同时间点采集样本，并通过组织学、RT-PCR和增殖试验进行分析。通过内膜/中膜比测量，SDF-1阻断导致新生内膜形成显著减少（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）。用NOX-A12体外处理原代血管平滑肌细胞显示出增殖的显著降低（0.42 ± 0.04 vs. 0.24 ± 0.03，P < 0.05）。SDF-1抑制后，TGF-β、TNF-α和IL-6水平明显降低（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在慢性移植物血管病变（CAV）的发展中起着关键作用。因此，用NOX-A12药理学抑制SDF-1可能是改善慢性排斥反应变化的治疗选择。
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.