Anti-fibrotic effects of p53 activation induced by RNA polymerase I inhibitor in primary cardiac fibroblasts

Abstract

Several lines of studies have indicated that the p53 pathway may have important anti-fibrotic functions. Previously we found that the novel selective RNA polymerase I inhibitor CX-5461 induced a robust response of p53 phosphorylation and activation in vascular smooth muscle cells. In the present study, we characterized the anti-fibrotic effects of CX-5461 in primary cardiac fibroblasts. We showed that CX-5461 suppressed spontaneous and mitogen-stimulated activation, proliferation, and myofibroblast differentiation, at a concentration (1 μM) with no cytotoxicity. The inhibitory effects of CX-5461 were primarily mediated by activation of the p53 pathway rather than limiting the rate of ribosome biogenesis. It was also shown that CX-5461 triggered a non-canonical DNA damage response in cardiac fibroblasts, which acted as the upstream signal leading to p53 activation. Taking these together, we suggest that p53 activation by pharmacological inhibition of Pol I may represent a viable approach to repress the development of cardiac fibrosis.

Keywords: CX-5461; Cardiac fibroblast; Myofibroblast; RNA polymerase I; p53.