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Nitric oxide mediates either proliferation or cell death in cardiomyocytes. Involvement of polyamines
C Pignatti1, B Tantini, C Stefanelli
1Department of Biochemistry G. Moruzzi, University of Bologna, Italy.
Abstract:
Nitric oxide (NO) is a molecule involved in several signal transduction pathways leading either to proliferation or to cell death. Induction of ornithine decarboxylase (ODC), the key enzyme of polyamine biosynthesis, represents an early event preceding DNA synthesis. In some cell types increased ODC activity seems to be involved in cytotoxic response. We investigated the role of NO and ODC induction on the events linked to cell proliferation or to cell death in cultured chick embryo cardiomyocytes. Exposure of cardiomyocytes to tumor necrosis factor (TNF) and lipopolysaccharide (LPS) caused NO synthase (NOS) and ODC induction as well as increased incorporation of [3H]-thymidine. This last effect was blocked by a NOS inhibitor and was strongly reduced by difluoromethylornithine (DFMO), an irreversible inhibitor of ODC. Sodium nitroprusside (SNP), an exogenous NO donor, inhibited the increases of NOS and ODC activities and abolished the mitogenic effect of TNF and LPS. Moreover, SNP alone caused cell death in a dose dependent manner. The cytotoxicity of SNP was not affected by DFMO while it was prevented by antioxidants. 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 inhibition and cell death, when NO is supplied as NO donor. Increased polyamine biosynthesis would mediate the proliferative response of NO, while the cytotoxicity of exogenous NO seems to involve some oxidative reactions and to depend on the balance between NO availability and cellular redox mechanisms.
Insights
Nitric oxide (NO) can promote cell proliferation via ornithine decarboxylase (ODC) induction in cardiomyocytes. However, exogenous NO donors can cause cell death through oxidative mechanisms, highlighting dual roles in cell fate.
Area of Science:
- Cardiovascular Biology
- Molecular Signaling
- Cell Death and Survival
Background:
- Nitric oxide (NO) is a crucial signaling molecule influencing cell proliferation and death.
- Ornithine decarboxylase (ODC) induction is an early event in DNA synthesis and may contribute to cytotoxic responses.
Purpose of the Study:
- To investigate the distinct roles of endogenous and exogenous nitric oxide (NO) in regulating cell proliferation and death in chick embryo cardiomyocytes.
- To elucidate the involvement of ornithine decarboxylase (ODC) induction in NO-mediated cellular responses.
Main Methods:
- Cultured chick embryo cardiomyocytes were treated with tumor necrosis factor (TNF), lipopolysaccharide (LPS), and sodium nitroprusside (SNP), an NO donor.
- Measurements included nitric oxide synthase (NOS) and ODC activity, [3H]-thymidine incorporation (DNA synthesis), and cell viability.
- Inhibitors of NOS and ODC (difluoromethylornithine - DFMO), as well as antioxidants, were used to probe signaling pathways.
Main Results:
- TNF and LPS induced NOS and ODC, increasing DNA synthesis, effects blocked by NOS inhibition and reduced by DFMO.
- Exogenous NO (SNP) inhibited TNF/LPS-induced NOS and ODC activity and abolished the mitogenic effect.
- SNP alone induced dose-dependent cell death, unaffected by DFMO but prevented by antioxidants, suggesting oxidative stress involvement.
Conclusions:
- Endogenous NO, via NOS induction, promotes cardiomyocyte proliferation linked to ODC activity and polyamine biosynthesis.
- Exogenous NO donors induce cell death through oxidative pathways, independent of ODC, and dependent on the cellular redox balance.
- NO exhibits dual signaling roles in cardiomyocytes, mediating either proliferation or cytotoxicity based on its source and cellular context.