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Investigation of the mechanisms activated by endogenous inhibitory pathways can lead to identification of novel targets for cardiovascular inflammatory pathologies. Here we exploited the potential protective role that melanocortin receptor type 3 (MC3-R) activation might play in a myocardial ischemia-reperfusion injury model. In resting conditions, mouse and rat heart extracts expressed MC3-R mRNA and protein, without changes following ischemia-reperfusion. At the cellular level heart macrophages, but not fibroblasts or cardiomyocytes, expressed this receptor, as demonstrated by immunogold labeling. In vivo, administration of the melanocortin agonist MTII (10 microg per mouse equivalent to 9.3 nmol) 30 min prior to ischemia (25 min) attenuated mouse heart 2 h reperfusion injury by approximately 40%, an effect prevented by the mixed MC3/4-R antagonist SHU9119 but not by the selective MC4-R antagonist HS204. Similar results were obtained when the compound was given at the beginning of the reperfusion period. Importantly, delayed myocardial damage as measured 24 h post-reperfusion was equally protected by administration of 10 microg MTII. The focus on MC3-R was also substantiated by analysis of the recessive yellow (e/e) mouse, bearing a mutated (inactive) MC1-R, in which MTII was fully protective. Myocardial protection was associated with reduced markers of systemic and local inflammation, including cytokine contents (interleukin-1 and KC) and myeloperoxidase activity. In conclusion, this study has highlighted a previously unrecognized protective role for MC3-R activation on acute and delayed heart reperfusion injury. These data may open new avenues for therapeutic intervention against heart and possibly other organ ischemia-reperfusion injury.

Original publication

DOI

10.1189/jlb.0306175

Type

Journal article

Journal

J Leukoc Biol

Publication Date

10/2004

Volume

76

Pages

845 - 853

Keywords

Acute Disease, Animals, Fibroblasts, Interleukin-1, Macrophages, Melanocyte-Stimulating Hormones, Mice, Mutation, Myocardial Infarction, Myocardial Reperfusion Injury, Myocardium, Myocytes, Cardiac, Peptides, Cyclic, Peroxidase, Rats, Receptor, Melanocortin, Type 3, Receptors, Corticotropin, alpha-MSH