Nitric oxide mediates either proliferation or cell death in cardiomyocytes. Involvement of polyamines

Nitric oxide (NO) is a molecule involved in several signal transduction pat hways leading either to proliferation or to cell death. Induction of ornith ine decarboxylase (ODC), the key enzyme of polyamine biosynthesis, represen ts an early event preceding DNA synthesis. In some cell types increased ODC activity seems to be involved in cytotoxic response. We investigated the r ole of NO and ODC induction on the events linked to cell proliferation or t o cell death in cultured chick embryo cardiomyocytes. Exposure of cardiomyo cytes to tumor necrosis factor (TNF) and lipopolysaccharide (LPS) caused NO synthase (NOS) and ODC induction as well as increased incorporation of [H- 3]-thymidine, This last effect was blocked by a NOS inhibitor and was stron gly reduced by difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. Sodium nitroprusside (SNP), an exogenous NO donor, inhibited the incr eases of NOS and ODC activities and abolished the mitogenic effect of TNF a nd LPS. Moreover, SNP alone caused cell death in a dose dependent manner. T he cytotoxicity of SNP was not affected by DFMO while it was prevented by a ntioxidants. The results suggest that different pathways would mediate the response of cardiomyocytes to NO: they can lead either to ODC induction and DNA synthesis when NO is formed through NOS induction or to growth inhibit ion and cell death, when NO is supplied as NO donor. Increased polyamine bi osynthesis would mediate the proliferative response of NO, while the cytoto xicity of exogenous NO seems to involve some oxidative reactions and to dep end on the balance between NO availability and cellular redox mechanisms.