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

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.