Stimulation of cardiac fibroblast proliferation by cerium: a superoxide anion-mediated response

Cardiac fibroblasts play a multifarious role in the maintenance of the func tional and structural integrity of the heart. Therefore inadvertent prolife ration of these fibroblasts can affect the normal functioning of the heart. The proliferation of fibroblasts could be due to various factors. We have worked on the hypothesis that low levels of cerium may stimulate cardiac fi broblasts to undergo proliferation and that free radicals act as the mediat ors of the stimulatory response. Cardiac fibroblasts isolated from neonatal Wistar rats were cultured. Proliferation of the cells was measured by cell count and immunohistochemical visualization for proliferating cell nuclear antigen, The response to cerium was assessed by comparison with control. A stimulatory response at low levels of cerium was observed with a peak at 0 .5 mu M concentration of cerium. A concomitant increase in the generation o f free radicals was also seen. The cerium-stimulated cell proliferation and free radical generation was neutralized by the inclusion of superoxide dis mutase in the culture medium. Conclusion: Low doses of cerium, at levels comparable to those found in the serum of patients with EMF, has a stimulatory effect on cardiac fibroblast s and the abrogation of proliferation by antioxidant superoxide dismutase i ndicates that superoxide anion acts as a biological intermediate in cerium- induced cardiac fibroblast proliferation. (C) 1999 Academic Press.