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

Abstract

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.

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

“…Potent inhibitory effects of CX-5461 against pathological arterial remodelling have been observed in our previous studies in rat carotid arteries and aortae with angioplasty-or transplantation-induced injuries (Dai et al, 2018;Ye et al, 2017). Based on these data and those from the present study, we suggest that the beneficial effects of CX- although G1/S blockade predominates in the latter comparing with G2/M blockade in the former (Ye et al, 2017).…”

“…It is clear that disruption of rDNA transcription triggers a distinct cellular stress response known as nucleolar stress, resulting in activation of the p53 pathway (Boulon et al, 2010;Yang et al, 2018). In contrast to the current paradigm which emphasizes stabilization and accumulation of p53 protein, following induction of nucleolar stress, we have repeatedly observed that CX-5461 had no major effects on total p53, but induced a robust response of p53 phosphorylation in a variety of cells (Dai et al, 2018;Ye et al, 2017), including human PASMCs, as used in the present study. Moreover, in the present study, we have confirmed that the cell cycle blockade in response to CX-5461 in human PASMCs is at least partly dependent on p53 as observed previously (Ye et al, 2017).…”

“…For instance, a recent study has shown that smooth muscle-specific p53 overexpression is not sufficient to rescue hypoxia-induced PAH (Wakasugi et al, 2019), indicating that p53 functions in other type(s) of cells (e.g., inflammatory cells as suggested by our previous observations) ( Dai et al, 2018) Representative western blots and densitometry data showing the in vivo effects of low-dose (12.5 mgÁkg −1 ) CX-5461 (CXL) on levels of phospho-p53 and total p53 in MCT-treated lungs (prevention cohort). Con, normal control.…”

“…NS, not significant. Dashed red lines indicate the position of blood vessels inhibit macrophage functions including activation, migration, proliferation and differentiation/maturation (Dai et al, 2018). The lung tissue contains a variety of subpopulations of macrophages, which may play differential roles in homeostasis and/or inflammation (Duan & Croft, 2014).…”

“…In particular, CX-5461 treatment resulted in a $ 50% decrease in the number of macrophages in PAH lungs. There is evidence suggesting that the macrophage is crucially involved in the pathogenesis of PAH, as macrophage depletion retards disease progression (Jankov et al, 2001;Zaloudikova et al, 2016 (Dai et al, 2018). The lung tissue contains a variety of subpopulations of macrophages, which may play differential roles in homeostasis and/or inflammation (Duan & Croft, 2014).…”