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

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Summary

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.

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References

  • Askew DS, Ashmun RA, Simmons BC, Cleveland JL (1991) Constitutivec-myc expression in an IL-3 dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene 6: 1915–1922

    Google Scholar 

  • Beauvais F, Michel L, Dubertret L (1995) The nitric oxide donors, azide and hydroxylamine, inhibit the programmed cell death of cytokine-deprived human eosinophils. FEBS Lett 361: 229–232

    Google Scholar 

  • Bishopric NH, Discher DJ, Webster KA (1997) Molecular correlates of the growth/death decision in cardiac myocytes. Cardiac cells in culture: molecular mechanisms of hypertrophy. Proceedings of the 2nd International Workshop, Ascona (Switzerland) 1997,

  • Blanco FJ, Ochs RL, Schwarz H, Lotz M (1995) Chondrocyte apoptosis induced by nitric oxide. Am J Pathol 146: 75–85

    Google Scholar 

  • Bradford MH (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye-binding. Anal Biochem 72: 248–254

    Google Scholar 

  • Colasanti M, Persichini T, Menegazzi M, Mariotto S, Giordano E, Caldarera CM, Sogos V, Lauro GM, Suzuki H (1995) Induction of nitric oxide synthase mRNA expression. J Biol Chem 270: 26731–26733

    Google Scholar 

  • Darley-Usmar V, Wiseman H, Halliwell B (1995) Nitric oxide and oxygen radicals: a question of balance. FEBS Lett 369: 131–135

    Google Scholar 

  • Dinerman JL, Lowenstein CJ, Snyder SH (1993) Molecular mechanisms of nitric oxide regulation. Circ Res 73: 217–222

    Google Scholar 

  • Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL (1992) Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257: 387–389

    Google Scholar 

  • Gardner PR, White CW (1996) Failure of tumor necrosis factor and interleukin-1 to elicit superoxide production in the mitochondrial matrices of mammalian cells. Arch Biochem Biophys 334: 158–162

    Google Scholar 

  • Giordano E, Giaccari A, Vaona I, Stefanelli C, Muscari C, Guarnieri C, Caldarera CM (1996) Exogenous nitric oxide inhibits iNOS induction by TNF/LPS in rat heart myocytes. J Mol Cell Cardiol 28: A35

    Google Scholar 

  • Golstein P, Ojcius D, Young DE (1991) Cell death in the immune system. Immunol Rev 121: 29–65

    Google Scholar 

  • Goossens V, Grooten J, De Vos K, Fiers W (1995) Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc Natl Acad Sci USA 92: 8115–8119

    Google Scholar 

  • Hirose K, Longo DL, Oppenheim JJ, Matsushima K (1993) Overexpression of mitochondrial manganese superoxide dismutase promotes the survival of tumor cells exposed to interleukin-1, tumor necrosis factor, selected anticancer drugs, and ionizing radiation. FASEB J 7: 361–368

    Google Scholar 

  • Hu J, Mahmoud MI, El-Fakahany EE (1994) Polyamines inhibit nitric oxide synthase in rat cerebellum. Neurosci Lett 175: 41–45

    Google Scholar 

  • Hurme M (1988) Both interleukin 1 and tumor necrosis factor enhance thymocyte proliferation. Eur J Immunol 18:1303–1306

    Google Scholar 

  • Inoue S, Kawanishi S (1995) Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBS Lett 371: 86–88

    Google Scholar 

  • Jacobson MD, Burne JF, Raff MC (1994) Mechanisms of programmed cell death and Bcl-2 protection. Biochem Soc Trans 22: 600–603

    Google Scholar 

  • Kitajima I, Kawahara K, Nakajima T, Soejima Y, Matsuyama T, Maruyama I (1994) Nitric oxide-mediated apoptosis in murine mastocytoma. Biochem Biophys Res Commun 204: 244–251

    Google Scholar 

  • Knowles RG, Moncada S (1994) Nitric oxide synthases in mammals. Biochem J 298: 249–258

    Google Scholar 

  • Kyriakis JM, Avruch J (1996) Protein kinase cascades activated by stress and inflammatory cytokines. BioEssays 18: 567–577

    Google Scholar 

  • Lin K-T, Xue J-Y, Nomen M, Spur B, Wong PY-K (1995) Peroxynitrite-induced apoptosis in HL-60 cells. J Biol Chem 270: 16487–16490

    Google Scholar 

  • Lipton SA, Chol Y, Pan Z, Lei SZ, Chen HV, Sucher NJ, Loscalzo J, Singel DJ, Stamler JS (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364: 626–632

    Google Scholar 

  • Manchester KM, Heston WDW, Donner DB (1993) Tumor necrosis factor-induced cytotoxicity is accompanied by intracellular mitogenic signals in ME-180 human cervical carcinoma cells. Biochem J 290: 185–190

    Google Scholar 

  • Morgan DML (1994) Difluoromethylornithine (DFMO), an inhibitor of nitrite production by macrophages? Biochem Soc Trans 22: 3895

    Google Scholar 

  • Nathan C (1992) Nitric oxide as a secretory product of mammalian cells. FASEB J 6: 3051–3064

    Google Scholar 

  • Nishio E, Fukushima K, Shiozaki M, Watanabe Y (1996) Nitric oxide donor SNAP induces apoptosis in smooth muscle cells through cGMP-independent mechanism. Biochem Biophys Res Commun 221: 163–168

    Google Scholar 

  • Ogura T, Tatemichi M, Esumi H (1997) Nitric oxide inhibits CPP32-like activity under redox regulation. Biochem Biophys Res Commun 236: 365–369

    Google Scholar 

  • Pignatti C, Tantini B, Sacchi P, Zanfanti ML, Clo C (1990) Effect of bacterial toxins on spermine-induced inhibition of adenylate cyclase activity of cultured heart cells. Cardioscience 1: 209–212

    Google Scholar 

  • Pinsky DJ, Cai B, Yang K, Rodriguez C, Sciacca RR, Cannon PJ (1995) The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factorβ. J Clin Invest 95: 677–685

    Google Scholar 

  • Polte T, Oberle S, Schroder H (1997) Nitric oxide protects endothelial cells from tumor necrosis factor-α-mediated cytotoxicity: possible involvement of cyclic GMP. FEBS Lett 409: 46–48

    Google Scholar 

  • Salgo MG, Pryor WA (1996) Trolox inhibits peroxynitrite mediated oxidative stress and apoptosis in rat thymocytes. Arch Biochem Biophys 333: 482–488

    Google Scholar 

  • Salgo MG, Squadrito GL, Pryor WA (1995) Peroxynitrite causes apoptosis in rat thymocytes. Biochem Biophys Res Commun 215: 1111–1118

    Google Scholar 

  • Sarih M, Souvannavong V, Adam A (1993) Nitric oxide synthase induces macrophage death by apoptosis. Biochem Biophys Res Commun 191: 503–508

    Google Scholar 

  • Schulz R, Nava E, Moncada S (1992) Induction and potential biological relevance of a Ca2+ independent nitric oxide synthase in the myocardium. Br J Pharmacol 105: 575–580

    Google Scholar 

  • Stein B, Frank P, Schmitz W, Schulz H, Thoenes M (1996) Endotoxins and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase. J Mol Cell Cardiol 28: 1631–1639

    Google Scholar 

  • Tabor CW, Tabor H (1984) Polyamines. Annu Rev Biochem 53: 749–790

    Google Scholar 

  • Toraason M, Luken ME, Krueger JA (1990) Cooperative action of insulin and cathecolamines on stimulation of ornithine decarboxylase activity in neonatal rat heart cells. J Mol Cell Cardiol 22: 637–644

    Google Scholar 

  • Umansky SR, Cuenco GM, Khutzian SS, Barr PJ, Tomei LD (1995) Post-ischemic apoptosic death of rat neonatal cardiomyocytes. Cell Death Differ 2: 235–241

    Google Scholar 

  • Van Heugten HAA, Bezstarosti K, Lamers JMJ (1994) Endothelin-1 and phenylephrine-induced activation of the phosphoinositide cycle increases cell injury of cultured cardiomyocytes exposed to hypoxia/reoxygenation. J Mol Cell Cardiol 26: 1513–1524

    Google Scholar 

  • Van Lint J, Agostini P, Vandevoorde V, Haegeman G, Fiers W, Merlevede W, Vandenheede JR (1992) Tumor necrosis factor stimulates multiple serine/threonine protein kinases in swiss 3T3 and L929 cells. J Biol Chem 267: 25916–25921

    Google Scholar 

  • Wu CF, Bishopric NH, Pratt RE (1997) Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem 272: 14860–14866

    Google Scholar 

  • Yang W, Ando J, Korenaga R, Toyo-oka T, Kamiya A (1994) Exogenous nitric oxide inhibits proliferation of cultured vascular endothelial cells. Biochem Biophys Res Commun 203: 1160–1167

    Google Scholar 

  • Ziche M, Morbidelli L, Masini E, Amerini S, Granger HJ, Maggi CA, Geppetti P, Ledda F (1994) Nitrix oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest 94: 2036–2044

    Google Scholar 

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Pignatti, C., Tantini, B., Stefanelli, C. et al. Nitric oxide mediates either proliferation or cell death in cardiomyocytes. Involvement of polyamines. Amino Acids 16, 181–190 (1999). https://doi.org/10.1007/BF01321535

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