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Lethal effect of cytokine-induced nitric oxide and peroxynitrite on cultured rat cardiac myocytes

Natsuya Keira1, Tetsuya Tatsumi, Satoaki Matoba

  • 1Second Department of Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.

Journal of Molecular and Cellular Cardiology
|June 12, 2002
PubMed

Insights

Cytokines induce nitric oxide (NO) production in heart cells, leading to cell death and energy depletion. Peroxynitrite formation mediates these harmful effects, suggesting therapeutic targets.

Area of Science:

  • Cardiovascular Biology
  • Immunology
  • Cellular Physiology

Background:

  • Cytokines like IL-1 beta, IFN-gamma, and LPS are known to induce inflammatory responses.
  • Nitric oxide (NO) plays complex roles in cardiovascular function, with both protective and detrimental effects.
  • Cardiac myocytes are susceptible to inflammatory insults, impacting myocardial function.

Purpose of the Study:

  • To investigate the cytotoxic effects of inducible nitric oxide synthase (iNOS)-generated NO in cultured cardiac myocytes stimulated by inflammatory cytokines.
  • To elucidate the role of peroxynitrite in cytokine-induced myocyte injury and energy depletion.
  • To evaluate the protective potential of peroxynitrite scavengers against cytokine-induced cardiac myocyte damage.

Main Methods:

  • Primary cardiac myocyte cultures were treated with IL-1 beta, IFN-gamma, and LPS.
  • Nitric oxide (NO) production was measured following cytokine treatment.
  • Cellular adenosine triphosphate (ATP) content and cell viability (necrosis) were assessed.
  • Immunohistochemistry was used to detect nitrotyrosine formation as a marker of peroxynitrite.
  • The effects of uric acid and L-cysteine (peroxynitrite quenchers) were evaluated.

Main Results:

  • Cytokine treatment for 48 hours significantly increased NO production in cardiac myocytes.
  • A marked decline in cellular ATP content and a significant increase in myocyte necrosis were observed.
  • Immunohistochemistry confirmed nitrotyrosine formation in cytokine-treated, injured myocytes.
  • Uric acid and L-cysteine attenuated myocyte death and nitrotyrosine formation but did not affect NO levels or ATP decline.
  • These findings indicate peroxynitrite mediates cytokine-induced myocyte necrosis.

Conclusions:

  • Cytokine-induced NO production contributes to cardiac myocyte injury and necrosis.
  • Peroxynitrite formation is a key mechanism underlying these detrimental effects.
  • Targeting peroxynitrite may offer a therapeutic strategy to protect cardiac myocytes from inflammatory damage.

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