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

Tamás Csont, Serena Viappiani, Jolanta Sawicka, Stephanie Slee, Judith Y. Altarejos, Ines Batinić-Haberle, Richard Schulz

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Pro-inflammatory cytokines have been shown to depress myocardial mechanical function by enhancing peroxynitrite generation in the heart. The contribution of NO synthesized by different NOS isoforms, as well as the contribution of superoxide to this mechanism are still not clear. Isolated working hearts of iNOS-/- and wildtype mice were perfused for 120:min in the presence or absence of a mixture of pro-inflammatory cytokines (IL-1β, TNF-α, and IFN-γ). iNOS mRNA was detected only in cytokine-treated wildtype hearts. In wildtype hearts, cytokine treatment significantly decreased cardiac work, calculated as cardiac output times peak systolic pressure, to 31 ± 9% of original values by the end of perfusion (P < 0.05). The decline of cardiac work induced by cytokine treatment was significantly reduced in iNOS-/- hearts (63 ± 5% of original value). Only cytokine-treated wildtype hearts showed decreased aconitase activity, indicating a higher level of oxidative stress in these hearts. Cytokines increased NADPH oxidase activity in both wildtype and iNOS-/- hearts, whereas NADH oxidase and xanthine oxidase/xanthine dehydrogenase activities were unaffected. The SOD mimetic MnTE2PyP prevented the cytokine-induced decline of cardiac work in both wildtype and iNOS-/- hearts. Cardiac p38 MAPK activation was unaltered in all experimental groups. Although genetic disruption of the iNOS gene provides partial protection against cytokine-induced cardiac dysfunction, iNOS-independent mechanisms, including contribution of NO from other NOS enzymes and the generation of superoxide, are also important contributors.

Original languageEnglish
Pages (from-to)833-840
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume39
Issue number5
DOIs
Publication statusPublished - Nov 1 2005

Keywords

  • Contractile function
  • Cytokines
  • Isolated working mouse heart
  • NADPH oxidase
  • Nitric oxide
  • SOD mimetics
  • Superoxide
  • iNOS knock-out mice

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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