Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury.

Academic Article

Abstract

  • Ischemia/reperfusion (I/R) injury is characterized by the induction of oxidative stress and proinflammatory cytokine expression. Recently demonstrating that oxidative stress and TNF-alpha each stimulate interleukin (IL)-18 expression in cardiomyocytes, we hypothesized that I/R also induces IL-18 expression and thus exacerbates inflammation and tissue damage. Neutralization of IL-18 signaling should therefore diminish tissue injury following I/R. I/R studies were performed using a chronically instrumented closed chest mouse model. Male C57BL/6 mice underwent 30 min of ischemia by LAD coronary artery ligation followed by various periods of reperfusion. Sham-operated or ischemia-only mice served as controls. A subset of animals was treated with IL-18-neutralizing antibodies 1 h prior to LAD ligation. Ischemic LV tissue was used for analysis. Our results demonstrate that, compared with sham operation and ischemia alone, I/R significantly increased (i) oxidative stress (increased MDA/4-HNE levels), (ii) neutrophil infiltration (increased MPO activity), (iii) NF-kappaB DNA binding activity (p50, p65), and (iv) increased expression of IL-18Rbeta, but not IL-18Ralpha or IL-18BP transcripts. Administration of IL-18-neutralizing antibodies significantly reduced I/R injury measured by reduced infarct size (versus control IgG). In isolated adult mouse cardiomyocytes, simulated ischemia/reperfusion enhanced oxidative stress and biologically active IL-18 expression via IKK-dependent NF-kappaB activation. These results indicate that IL-18 plays a critical role in I/R injury and thus represents a promising therapeutic target.
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    Keywords

  • Animals, Antibodies, Gene Expression Regulation, Heart Ventricles, Inflammation, Inflammation Mediators, Interleukin-18, Male, Mice, Myocardial Reperfusion Injury, Myocytes, Cardiac, NF-kappa B, Neutrophil Infiltration, Oxidative Stress, Signal Transduction, Tumor Necrosis Factor-alpha
  • Digital Object Identifier (doi)

    Author List

  • Venkatachalam K; Prabhu SD; Reddy VS; Boylston WH; Valente AJ; Chandrasekar B
  • Start Page

  • 7853
  • End Page

  • 7865
  • Volume

  • 284
  • Issue

  • 12