Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury.
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.
Venkatachalam
Kaliyamurthi
K
Department of Veterans Affairs South Texas Veterans Health Care System and the Departments of Medicine and Surgery, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
Prabhu
Sumanth D
SD
Reddy
Venkatapuram Seenu
VS
Boylston
William H
WH
Valente
Anthony J
AJ
Chandrasekar
Bysani
B
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020382:Interleukin-18 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000906:Antibodies; D018836:Inflammation Mediators; D020382:Interleukin-18; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha