Melanocortins counteract inflammatory and apoptotic responses to prolonged myocardial ischemia/reperfusion through a vagus nerve-mediated mechanism.

Abstract

Recently we reported that an efferent vagal fibre-mediated cholinergic protective pathway, activated by melanocortins acting at brain melanocortin MC(3) receptors, is operative in a condition of short-term myocardial ischemia/reperfusion associated with a high incidence of severe arrhythmias and death. Here we investigated melanocortin effects, and the role of the vagus nerve-mediated cholinergic protective pathway, in a rat model of prolonged myocardial ischemia/reperfusion associated with marked inflammatory and apoptotic reactions, and a large infarct size. Ischemia was produced in rats by ligature of the left anterior descending coronary artery for 30 min. At the end of the 2-h reperfusion, western blot analysis of the inflammatory and apoptotic markers tumor necrosis factor-alpha (TNF-alpha), c-jun N-terminal kinases (JNK) and caspase-3, as well as of the anti-apoptotic extracellular signal-regulated kinases (ERK 1/2), was performed in the left ventricle. In saline-treated ischemic rats there was an increase in TNF-alpha levels and in the activity of JNK and caspase-3 accompanied, despite an appreciable ERK 1/2 activation, by a large infarct size. Intravenous treatment, during coronary artery occlusion, with the melanocortin analog [Nle(4), D-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) produced a reduction in TNF-alpha levels and in the activity of JNK and caspase-3, associated with marked activation of the pro-survival kinases ERK 1/2, and consequent attenuation of infarct size. Bilateral cervical vagotomy blunted the protective effects of NDP-alpha-MSH. These results indicate that melanocortins modulate the inflammatory and apoptotic cascades triggered by prolonged myocardial ischemia/reperfusion, and reduce infarct size, seemingly by activation of the vagus nerve-mediated cholinergic protective pathway.

• Authors: Alessandra Ottani, Daniela Giuliani, Maria Galantucci, Luca Spaccapelo, Ettore Novellino, Paolo Grieco, Jerzy Jochem, Salvatore Guarini
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 637 Issue 1-3 Pg. 124-30 (Jul 10 2010) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 20385118 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier B.V. All rights reserved.

Chemical References

• Melanocortins
• Tumor Necrosis Factor-alpha
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Caspase 3 (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Inflammation (drug therapy, pathology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Male
• Melanocortins (pharmacology, therapeutic use)
• Myocardial Reperfusion Injury (drug therapy, enzymology, metabolism, pathology)
• Rats
• Rats, Wistar
• Time Factors
• Tumor Necrosis Factor-alpha (metabolism)
• Vagus Nerve (drug effects, physiology)