Development of Chronic Heart Failure Model Caused by Inflammatory Cytokines and Establishment of Prophylactic and Therapeutic Strategies for the Heart Failure

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(1)We have developed a canine model of sustained myocardial dysfunction, in which interleukin-1beta (lL-1beta) bound to microspeheres (MS) was selectively injected into the left main coronary artery. This novel model is unique as the long-term effect of an inflammatory cytokine on the heart can be examined without causing its systemic effect. In this model, sustained left ventricular (LV) dysfunction was noted in animals that received IL-1beta-MS but not in those that received MS alone.(2)First, the role of adhesion molecules was examined. When the adhesion molecule inhibitor, SLeX-oligosaccharide (SLeX-OS), or the P-selectin inhibitor, PB1.3, was pre-administered, the leukocyte infiltration and sustained LV dysfunction caused by IL-1beta were markedly inhibited, indicating the important role of adhesion molecules in this model.(3)Second, the role of nitric oxide (NO) derived from inducible NO synthase (iNOS) was examined. When the non-specific protein synthase inhibitor, dexamethasone … More (DEX), or the iNOS inhibitor, aminoguanidine (AG), was pre-administered, the IL-beta-induced sustained myocardial dysfunction was markedly prevented, indicating the important role of iNOS-derived NO in the pathogenesis of the myocardial dysfunction in this model.(4)Third, the role of superoxide anion was examined. When the superoxide anion synthesis inhibitor, OPC-6535, was pre-administered, the IL-1beta-induced sustained myocardial dysfunction was markedly prevented, indicating that superoxide anion may also play an important role in our model.(5)Finally, we measured the myocardial concentrations of nitrotyrosine as a marker for peroxynitrite production as a result of the interaction between NO and superoxide anion. Superoxide anion is known to be a more cytotoxic factor than NO or superoxide anion. The results showed that nitrotyrosine formation was increased in the IL-beta group, whereas the formation was markedly inhibited in the SLeX-OS, PB 1.3, DEX, AG, and OPC-6535 groups. There was a significant correlation between he myocardial concentrations of nitrotyrosine and LV dysfunction, indicating that peroxynitrite is at least one of the major causative factors for the myocardial dysfunction in our model in vivo. Less