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Updated: Mar 9, 2026
A Rat Carotid Artery Pressure-Controlled Segmental Balloon Injury with Periadventitial Therapeutic Application
Published on: July 9, 2020
Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced
Qing Ye1, Shu Pang1, Wenjing Zhang1
1From 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.).
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.
Insights
Targeting RNA polymerase I (Pol I) with CX-5461 inhibits neointimal hyperplasia after arterial injury. This therapeutic strategy prevents smooth muscle cell proliferation by activating the ATR-p53 pathway, offering a novel approach for arterial restenosis.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Cell Cycle Regulation
Background:
- Ribosome biogenesis, driven by RNA polymerase I (Pol I), is crucial for cell proliferation.
- Dysregulated Pol I activity's role in cardiovascular disease is largely unrecognized.
- Neointimal hyperplasia following arterial injury contributes to restenosis.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting Pol I in preventing arterial injury-induced neointimal hyperplasia.
- To elucidate the molecular mechanisms underlying Pol I inhibition's effects on vascular smooth muscle cells.
Main Methods:
- Utilized CX-5461, a selective Pol I inhibitor, in a rat carotid artery balloon injury model.
- Assessed neointima formation, smooth muscle cell proliferation, and apoptosis in vivo and in vitro.
- Investigated the involvement of the ATR-p53 signaling pathway and cell cycle regulators.
Main Results:
- Local Pol I inhibition with CX-5461 significantly blocked neointima formation in vivo.
- CX-5461 induced G2/M cell cycle arrest in proliferating smooth muscle cells without significant apoptosis.
- The drug activated the ataxia telangiectasia mutated/ataxia telangiectasia and Rad3-related (ATR)-p53 axis, leading to increased p53 phosphorylation and acetylation.
Conclusions:
- Pol I is a viable therapeutic target for inhibiting neointimal hyperplasia and preventing arterial restenosis.
- Pol I inhibition promotes smooth muscle cell cycle arrest through the ATR-p53 pathway.
- Targeting Pol I offers a novel strategy for managing cardiovascular diseases characterized by vascular remodeling.
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