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The involvement of superoxide and iNOS-derived NO in cardiac dysfunction induced by pro-inflammatory cytokines

Tamás Csont1, Serena Viappiani, Jolanta Sawicka

  • 1Cardiovascular Research Group, Department of Pharmacology and Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, 4-62 HMRC, Edmonton, AB, Canada T6G 2S2.

Journal of Molecular and Cellular Cardiology
|September 21, 2005
PubMed

Insights

Pro-inflammatory cytokines impair heart function, partly via inducible nitric oxide synthase (iNOS). However, iNOS-independent pathways involving superoxide also contribute significantly to cytokine-induced cardiac dysfunction.

Area of Science:

  • Cardiovascular Research
  • Molecular Cardiology
  • Oxidative Stress Biology

Background:

  • Pro-inflammatory cytokines (IL-1beta, TNF-alpha, IFN-gamma) depress myocardial function by increasing peroxynitrite generation.
  • The specific roles of nitric oxide (NO) from different nitric oxide synthase (NOS) isoforms and superoxide in this process remain unclear.

Purpose of the Study:

  • To investigate the contribution of inducible nitric oxide synthase (iNOS) and other mechanisms to cytokine-induced cardiac dysfunction.
  • To elucidate the roles of NO and superoxide in myocardial mechanical depression caused by inflammatory cytokines.

Main Methods:

  • Isolated working hearts from iNOS knockout and wildtype mice were perfused with or without pro-inflammatory cytokines.
  • Assessed cardiac work, aconitase activity (oxidative stress marker), NADPH oxidase activity, and p38 MAPK activation.
  • Utilized a superoxide dismutase (SOD) mimetic (MnTE2PyP) to evaluate the role of superoxide.

Main Results:

  • Cytokine treatment significantly reduced cardiac work in wildtype hearts, an effect partially attenuated in iNOS knockout hearts.
  • Only cytokine-treated wildtype hearts showed decreased aconitase activity, indicating increased oxidative stress.
  • Cytokines increased NADPH oxidase activity in both genotypes, and the SOD mimetic protected against cardiac dysfunction in both groups.

Conclusions:

  • Genetic disruption of iNOS offers partial protection against cytokine-induced cardiac dysfunction.
  • iNOS-independent mechanisms, including NO from other NOS isoforms and superoxide generation, are crucial contributors to inflammatory cardiac dysfunction.
  • Superoxide generation, partly via NADPH oxidase, plays a significant role in cytokine-induced myocardial impairment.

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