Polyamines, NO and cGMP mediate stimulation of DNA synthesis by tumor necrosis factor and lipopolysaccharide in chick embryo cardiomyocytes

doi:10.1016/S0008-6363(00)00255-8

Cardiovascular Research 2001 49(2):408-416; doi:10.1016/S0008-6363(00)00255-8
© 2001 by European Society of Cardiology

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Polyamines, NO and cGMP mediate stimulation of DNA synthesis by tumor necrosis factor and lipopolysaccharide in chick embryo cardiomyocytes

Benedetta Tantini^a^,*, Flavio Flamigni^a, Carla Pignatti^a, Claudio Stefanelli^a, Monia Fattori^a, Annalisa Facchini^a, Emanuele Giordano^a, Carlo Clô^b and Claudio Marcello Caldarera^a

^aDepartment of Biochemistry "G.Moruzzi", School of Medicine, University of Bologna, via Irnerio, 48 40126 Bologna, Italy
^bInstitute of Biological Chemistry, School of Medicine, University of Parma, Parma, Italy

^* Corresponding author. Tel.: +39-51-209-1225; fax: +39-51-209-1224 tantini{at}biocfarm.unibo.it

Objective: We have recently shown that tumor necrosis factor- ${alpha}$ (TNF ${alpha}$ ) and lipopolysaccharide (LPS) stimulate DNA synthesis inchick embryo cardiomyocytes (CMs). The aim of the present researchwas to investigate the pathways involved in this mitogenic response.Methods: CMs were isolated from 10-day-old chick embryos andgrown to confluence. After 20 h of serum starvation the cellswere treated with TNF ${alpha}$ and LPS, and/or specific agonists andantagonists to manipulate the levels of polyamines, NO, cGMPand their biosynthetic enzymes ornithine decarboxylase (ODC),nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC).ODC, NOS, sGC activities and cGMP contents were determined byradiochemical procedures. DNA synthesis was determined by incorporationof [³H]-thymidine. Results: Treatment of CMs with TNF ${alpha}$ and LPSincreased cell number and [³H]-thymidine incorporation. Additionof TNF ${alpha}$ and LPS provoked an induction of ODC, with consequentpolyamine accumulation, and a more delayed enhancement of NOSactivity, which appeared to be independent of the activationof the ODC–polyamine system. TNF ${alpha}$ and LPS treatment alsoenhanced cGMP level in CMs and both polyamine and NO biosynthesesappeared to be required. Experiments with specific inhibitorsof ODC and NOS, as well as with inhibitors of sGC and cGMP-dependentprotein kinase (PKG), showed that polyamine-, NO- and cGMP-dependentpathways are required for the mitogenic action of TNF ${alpha}$ and LPS.Moreover, addition of exogenous polyamines to untreated cellsraised the cGMP level in a NO-dependent fashion, and enhanced[³H]-thymidine incorporation. The latter effect was inhibitedby sGC or PKG inhibitors. Treatment of quiescent cells withNO donors, 8-bromo-cGMP or YC-1, an sGC activator, also promotedDNA synthesis. Furthermore, putrescine and NO donor can additivelyactivate sGC in cell-free extracts. Conclusion: TNF ${alpha}$ and LPSstimulate DNA synthesis in chick embryo CMs and this effectis mediated by polyamines, NO and intracellular cGMP.

KEYWORDS Cytokines; Myocytes; Nitric oxide; Second messengers

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