The selective RNA polymerase I inhibitor CX-5461 mitigates neointimal remodeling in a modified model of rat aortic transplantation

Background 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. Methods 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 peri-vascular release. Results 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. Conclusions In conclusion, our results suggest that pharmacological inhibition of Pol I may be a novel strategy to treat transplantation-induced arterial remodeling. Received 11 January 2018. Revision received 27 June 2018. Accepted 29 June 2018. These authors contributed equally to the work, Chaochao Dai, MBBS, Mengyao Sun. Address correspondence to: Dr. Fan Jiang (fjiang@sdu.edu.cn) or Dr. Jianli Wang (wangmaq@sdu.edu.cn), School of Basic Medicine, Shandong University, 44 Wen Hua Xi Road, Jinan, Shandong Province 250012, China. Phone: +86 531 8838 2044; Fax +86 531 8295 9051 Conflict of interest declaration: none Author contributions: Chaochao Dai: performed experiments; did data acquisition and analysis; involved in drafting the manuscript Mengyao Sun: performed experiments; did data acquisition and analysis; involved in drafting the manuscript Fengjiao Wang: performed experiments and data acquisition/analysis Jiankang Zhu: performed experiments and data acquisition/analysis Yaping Wei: performed experiments and data acquisition/analysis Xiaotong Guo: performed experiments and data acquisition/analysis Siqin Ma: participated in data acquisition and analysis Bo Dong: participated in data acquisition and analysis Gejin Wang: participated in data acquisition and analysis Fan Jiang: conceived the study; provided intellectual inputs for data interpretations; revised the manuscript Jianli Wang: conceived the study; provided intellectual inputs for data interpretations Funding support This study was supported by grants from Natural Science Foundation of China (91539102 and 31471087 for F.J.; 81500496 for J.Z.), National 973 Basic Research Program (2010CB732605 for F.J.), Natural Science Foundation of Shandong Province (No. ZR2016HM24 for J.W.) and University Innovation Fund of Jinan City (201401251 for J.W.). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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