Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, Shandong Province, China.
School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
Transplantation. 2018 Oct;102(10):1674-1683. doi: 10.1097/TP.0000000000002372.
Transplant vasculopathy is a major cause of chronic rejection of transplanted organs. In the present study, we examined the effects of CX-5461, a novel selective inhibitor of RNA polymerase I, on development of transplant vasculopathy using a modified model of rat aortic transplantation.
The thoracic aortas from Fischer rats were transplanted into the abdominal cavity of Lewis rats. CX-5461 was mixed in pluronic gel and administered via perivascular release.
Treatment with CX-5461 mitigated the development of neointimal hyperplasia and vascular inflammation. This effect was likely to be attributable in part to inhibition of macrophage-dependent innate immunity reactions. Specifically, CX-5461 exhibited potent inhibitory effects on macrophage migration and lipopolysaccharide-induced activation. Treatment with CX-5461 also prevented macrophage differentiation and maturation from primary bone marrow cells. In macrophages, CX-5461 did not alter the total amount of p53 protein, but significantly increased p53 phosphorylation, which was involved in regulating cytokine-stimulated macrophage proliferation.
In conclusion, our results suggest that pharmacological inhibition of RNA polymerase I may be a novel strategy to treat transplantation-induced arterial remodeling.
移植血管病是移植器官慢性排斥反应的主要原因。在本研究中，我们使用改良的大鼠主动脉移植模型，研究了新型 RNA 聚合酶 I 选择性抑制剂 CX-5461 对移植血管病发展的影响。
将 Fischer 大鼠的胸主动脉移植到 Lewis 大鼠的腹腔中。CX-5461 与 pluronic 凝胶混合，并通过血管周围释放进行给药。
CX-5461 治疗减轻了新生内膜增生和血管炎症的发展。这种作用可能部分归因于抑制巨噬细胞依赖性固有免疫反应。具体而言，CX-5461 对巨噬细胞迁移和脂多糖诱导的激活具有强大的抑制作用。CX-5461 治疗还可防止原代骨髓细胞中巨噬细胞的分化和成熟。在巨噬细胞中，CX-5461 不会改变 p53 蛋白的总量，但会显著增加 p53 磷酸化，这与调节细胞因子刺激的巨噬细胞增殖有关。
总之，我们的结果表明，RNA 聚合酶 I 的药理抑制可能是治疗移植诱导的动脉重塑的一种新策略。
