Therapeutic efficacy of the novel selective RNA polymerase I inhibitor CX-5461 on pulmonary arterial hypertension and associated vascular remodelling

Abstract

Background and Purpose: CX-5461 is a novel selective RNA polymerase I (Pol I) inhibitor. Previously, we found that CX-5461 could inhibit pathological arterial remodelling caused by angioplasty and transplantation. In the present study, we explored the pharmacological effects of CX-5461 on experimental pulmonary arterial hypertension (PAH) and PAH-associated vascular remodelling. Experimental Approach: PAH was induced in Sprague–Dawley rats by monocrotaline or Sugen/hypoxia. Key Results: We demonstrated that CX-5461 was well tolerated for in vivo treatments. CX-5461 prevented the development of pulmonary arterial remodelling, perivascular inflammation, pulmonary hypertension, and improved survival. More importantly, CX-5461 partly reversed established pulmonary hypertension. In vitro, CX-5461 induced cell cycle arrest in human pulmonary arterial smooth muscle cells. The beneficial effects of CX-5461 in vivo and in vitro were associated with increased activation (phosphorylation) of p53. Conclusion and Implications: Our results suggest that pharmacological inhibition of Pol I may be a novel therapeutic strategy to treat otherwise drug-resistant PAH.