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The Selective RNA Polymerase I Inhibitor CX-5461 Mitigates Neointimal Remodeling in a Modified Model of Rat Aortic Transplantation

Dai, Chaochao, MBBS1; Sun, Mengyao, MBBS1; Wang, Fengjiao, MBBS2; Zhu, Jiankang, MD3; Wei, Yaping, MBBS1; Guo, Xiaotong, MBBS1; Ma, Siqin, MBBS4; Dong, Bo, MD5; Wang, Gejin6; Jiang, Fan, PhD1,7; Wang, Jianli, PhD1

doi: 10.1097/TP.0000000000002372
Original Basic Science—General

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 perivascular 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 RNA polymerase I may be a novel strategy to treat transplantation-induced arterial remodeling.

The authors explore the therapeutic potential of a novel selective inhibitor of RNA polymerase I on attenuation of transplant vasculopathy in a modified model of rat aortic transplantation. The pharmacological inhibition of RNA polymerase I may prevent cytokine-stimulated macrophage proliferation.

1 Department of Physiology and Pathophysiology, School of Basic Medicine, Shandong University, Jinan, Shandong Province, China.

2 School of Medicine and Life Sciences, University of Jinan, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.

3 Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, China.

4 School of Stomatology, Peking University, Beijing, China.

5 Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China.

6 Zibo Vocational Institute, Zibo, Shandong Province, China.

7 Key Laboratory of Cardiovascular Remodeling and Function Research (Chinese Ministry of Education and Chinese Ministry of Health) and State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong Province, China.

Received 11 January 2018. Revision received 27 June 2018.

Accepted 29 June 2018.

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.).

The authors declare no conflicts of interest.

C.D. performed experiments, did data acquisition and analysis, involved in drafting the article. M.S. performed the experiments; did data acquisition and analysis; involved in drafting the article. F.W. performed the experiments and data acquisition/analysis. J.Z. performed experiments and data acquisition/analysis. Y.W. performed experiments and data acquisition/analysis. X.G. performed experiments and data acquisition/analysis. S.M. participated in data acquisition and analysis. B.D. participated in data acquisition and analysis. G.W. participated in data acquisition and analysis. F.J. conceived the study, provided intellectual inputs for data interpretations, revised the article. J.W. conceived the study and provided intellectual inputs for data interpretations. C.D. and M.S. contributed equally to the work.

Correspondence: Fan Jiang, PhD, School of Basic Medicine, Shandong University, 44 Wen Hua Xi Road, Jinan, Shandong Province 250012, China. (fjiang@sdu.edu.cn); Jianli Wang, PhD, School of Basic Medicine, Shandong University, 44 Wen Hua Xi Road, Jinan, Shandong Province 250012, China.(wangmaq@sdu.edu.cn).

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

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