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Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced Neointimal Hyperplasia.
Arterioscler Thromb Vasc Biol. 2017 Mar; 37(3):476-484.AT

Abstract

OBJECTIVE

RNA polymerase I (Pol I)-dependent rRNA synthesis is a determinant factor in ribosome biogenesis and thus cell proliferation. The importance of dysregulated Pol I activity in cardiovascular disease, however, has not been recognized. Here, we tested the hypothesis that specific inhibition of Pol I might prevent arterial injury-induced neointimal hyperplasia.

APPROACH AND RESULTS

CX-5461 is a novel selective Pol I inhibitor. Using this tool, we demonstrated that local inhibition of Pol I blocked balloon injury-induced neointima formation in rat carotid arteries in vivo. Neointimal development was associated with augmented rDNA transcriptional activity as evidenced by the increased phosphorylation of upstream binding factor-1. The beneficial effect of CX-5461 was mainly mediated by inducing G2/M cell cycle arrest of proliferating smooth muscle cells without obvious apoptosis. CX-5461 did not induce p53 stabilization but increased p53 phosphorylation and acetylation and activated the ataxia telangiectasia mutated/ataxia telangiectasia and Rad3-related (ATR) pathway. Inhibition of ATR, but not of ataxia telangiectasia mutated, abolished the cytostatic effect of CX-5461 and p53 phosphorylation. In addition, inhibition of p53 or knockdown of the p53 target GADD45 mimicked the effect of ATR inhibition. In vivo experiments showed that the levels of phospho-p53 and acetyl-p53, and activity of the ataxia telangiectasia mutated/ATR pathway were all augmented in CX-5461-treated vessels.

CONCLUSIONS

Pol I can be therapeutically targeted to inhibit the growth of neointima, supporting that Pol I is a novel biological target for preventing arterial restenosis. Mechanistically, Pol I inhibition elicited G2/M cell cycle arrest in smooth muscle cells via activation of the ATR-p53 axis.

Authors+Show Affiliations

From the School of Basic Medicine, Shandong University, Jinan, Shandong Province, China (Q.Y., S.P., W.Z., X.G., J.W., Y.L., F.J.); Key Laboratory of Cardiovascular Remodeling and Function Research & The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China (X.W.); and Department of Cardiology, Qing Dao Central Hospital, Qing Dao, Shandong Province, China (Y.Z.).From the School of Basic Medicine, Shandong University, Jinan, Shandong Province, China (Q.Y., S.P., W.Z., X.G., J.W., Y.L., F.J.); Key Laboratory of Cardiovascular Remodeling and Function Research & The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China (X.W.); and Department of Cardiology, Qing Dao Central Hospital, Qing Dao, Shandong Province, China (Y.Z.).From the School of Basic Medicine, Shandong University, Jinan, Shandong Province, China (Q.Y., S.P., W.Z., X.G., J.W., Y.L., F.J.); Key Laboratory of Cardiovascular Remodeling and Function Research & The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China (X.W.); and Department of Cardiology, Qing Dao Central Hospital, Qing Dao, Shandong Province, China (Y.Z.).From the School of Basic Medicine, Shandong University, Jinan, Shandong Province, China (Q.Y., S.P., W.Z., X.G., J.W., Y.L., F.J.); Key Laboratory of Cardiovascular Remodeling and Function Research & The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China (X.W.); and Department of Cardiology, Qing Dao Central Hospital, Qing Dao, Shandong Province, China (Y.Z.).From the School of Basic Medicine, Shandong University, Jinan, Shandong Province, China (Q.Y., S.P., W.Z., X.G., J.W., Y.L., F.J.); Key Laboratory of Cardiovascular Remodeling and Function Research & The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China (X.W.); and Department of Cardiology, Qing Dao Central Hospital, Qing Dao, Shandong Province, China (Y.Z.).From the School of Basic Medicine, Shandong University, Jinan, Shandong Province, China (Q.Y., S.P., W.Z., X.G., J.W., Y.L., F.J.); Key Laboratory of Cardiovascular Remodeling and Function Research & The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China (X.W.); and Department of Cardiology, Qing Dao Central Hospital, Qing Dao, Shandong Province, China (Y.Z.).From the School of Basic Medicine, Shandong University, Jinan, Shandong Province, China (Q.Y., S.P., W.Z., X.G., J.W., Y.L., F.J.); Key Laboratory of Cardiovascular Remodeling and Function Research & The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China (X.W.); and Department of Cardiology, Qing Dao Central Hospital, Qing Dao, Shandong Province, China (Y.Z.).From the School of Basic Medicine, Shandong University, Jinan, Shandong Province, China (Q.Y., S.P., W.Z., X.G., J.W., Y.L., F.J.); Key Laboratory of Cardiovascular Remodeling and Function Research & The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China (X.W.); and Department of Cardiology, Qing Dao Central Hospital, Qing Dao, Shandong Province, China (Y.Z.).From the School of Basic Medicine, Shandong University, Jinan, Shandong Province, China (Q.Y., S.P., W.Z., X.G., J.W., Y.L., F.J.); Key Laboratory of Cardiovascular Remodeling and Function Research & The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China (X.W.); and Department of Cardiology, Qing Dao Central Hospital, Qing Dao, Shandong Province, China (Y.Z.). fjiang@sdu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28062495

Citation

Ye, Qing, et al. "Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced Neointimal Hyperplasia." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 37, no. 3, 2017, pp. 476-484.
Ye Q, Pang S, Zhang W, et al. Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced Neointimal Hyperplasia. Arterioscler Thromb Vasc Biol. 2017;37(3):476-484.
Ye, Q., Pang, S., Zhang, W., Guo, X., Wang, J., Zhang, Y., Liu, Y., Wu, X., & Jiang, F. (2017). Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced Neointimal Hyperplasia. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(3), 476-484. https://doi.org/10.1161/ATVBAHA.116.308401
Ye Q, et al. Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced Neointimal Hyperplasia. Arterioscler Thromb Vasc Biol. 2017;37(3):476-484. PubMed PMID: 28062495.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced Neointimal Hyperplasia. AU - Ye,Qing, AU - Pang,Shu, AU - Zhang,Wenjing, AU - Guo,Xiaotong, AU - Wang,Jianli, AU - Zhang,Yongtao, AU - Liu,Yang, AU - Wu,Xiao, AU - Jiang,Fan, Y1 - 2017/01/05/ PY - 2016/09/02/received PY - 2016/12/21/accepted PY - 2017/1/8/pubmed PY - 2017/6/22/medline PY - 2017/1/8/entrez KW - RNA polymerase I KW - ataxia telangiectasia KW - cell cycle checkpoints KW - muscle, smooth KW - neointima SP - 476 EP - 484 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler. Thromb. Vasc. Biol. VL - 37 IS - 3 N2 - OBJECTIVE: RNA polymerase I (Pol I)-dependent rRNA synthesis is a determinant factor in ribosome biogenesis and thus cell proliferation. The importance of dysregulated Pol I activity in cardiovascular disease, however, has not been recognized. Here, we tested the hypothesis that specific inhibition of Pol I might prevent arterial injury-induced neointimal hyperplasia. APPROACH AND RESULTS: CX-5461 is a novel selective Pol I inhibitor. Using this tool, we demonstrated that local inhibition of Pol I blocked balloon injury-induced neointima formation in rat carotid arteries in vivo. Neointimal development was associated with augmented rDNA transcriptional activity as evidenced by the increased phosphorylation of upstream binding factor-1. The beneficial effect of CX-5461 was mainly mediated by inducing G2/M cell cycle arrest of proliferating smooth muscle cells without obvious apoptosis. CX-5461 did not induce p53 stabilization but increased p53 phosphorylation and acetylation and activated the ataxia telangiectasia mutated/ataxia telangiectasia and Rad3-related (ATR) pathway. Inhibition of ATR, but not of ataxia telangiectasia mutated, abolished the cytostatic effect of CX-5461 and p53 phosphorylation. In addition, inhibition of p53 or knockdown of the p53 target GADD45 mimicked the effect of ATR inhibition. In vivo experiments showed that the levels of phospho-p53 and acetyl-p53, and activity of the ataxia telangiectasia mutated/ATR pathway were all augmented in CX-5461-treated vessels. CONCLUSIONS: Pol I can be therapeutically targeted to inhibit the growth of neointima, supporting that Pol I is a novel biological target for preventing arterial restenosis. Mechanistically, Pol I inhibition elicited G2/M cell cycle arrest in smooth muscle cells via activation of the ATR-p53 axis. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/28062495/Therapeutic_Targeting_of_RNA_Polymerase_I_With_the_Small_Molecule_CX_5461_for_Prevention_of_Arterial_Injury_Induced_Neointimal_Hyperplasia_ L2 - http://www.ahajournals.org/doi/full/10.1161/ATVBAHA.116.308401?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -