cx-5461 and Arteriosclerosis

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.. 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.. 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.. In conclusion, our results suggest that pharmacological inhibition of RNA polymerase I may be a novel strategy to treat transplantation-induced arterial remodeling.

Topics: Allografts; Animals; Aorta; Aortic Diseases; Arteriosclerosis; Benzothiazoles; Cell Movement; Disease Models, Animal; Enzyme Inhibitors; Heart Transplantation; Humans; Macrophages; Male; Mice; Mice, Inbred C57BL; Naphthyridines; Neointima; Primary Cell Culture; Rats; Rats, Inbred F344; RAW 264.7 Cells; RNA Polymerase I; Treatment Outcome; Vascular Remodeling