NDP-α-MSH attenuates heart and liver responses to myocardial reperfusion via the vagus nerve and JAK/ERK/STAT signaling.

Abstract

Melanocortin peptides afford cardioprotection during myocardial ischemia/reperfusion via janus kinases (JAK), extracellular signal-regulated kinases (ERK) and signal transducers/activators of transcription (STAT) pathways. Here we investigated whether melanocortin-induced modulation of the JAK/ERK/STAT signaling occurs via the cholinergic anti-inflammatory pathway, focusing our study on cardiac and hepatic responses to prolonged myocardial ischemia/reperfusion. Ischemia was produced in rats by ligature of the left anterior descending coronary artery for 30min; effects of ischemia/reperfusion were evaluated using Western blot of heart and liver proteins. Intravenous treatment, during coronary artery occlusion, with the melanocortin analog (Nle(4), D-Phe(7))α-melanocyte-stimulating hormone (NDP-α-MSH) induced a left ventricle up-regulation of the cardioprotective transcription factors pJAK2, pERK1/2 and pTyr-STAT3 (JAK-dependent), and a reduction in the levels of the inflammatory mediators tumor necrosis factor-α (TNF-α) and pJNK (a transcription factor also involved in apoptosis), as assessed at the end of the 2-h reperfusion period. Further, these beneficial effects of NDP-α-MSH were associated with heart over-expression of the pro-survival proteins heme oxygenase-1 (HO-1) and Bcl-XL, and decrease of ventricular arrhythmias and infarct size. In the liver NDP-α-MSH induced a decrease in the pJAK2 and pTyr-STAT3 levels, and strongly reduced pERK1/2 expression. In the liver of ischemic rats NDP-α-MSH also blunted pJNK activity and TNF-α expression, and up-regulated Bcl-XL. Bilateral cervical vagotomy prevented all effects of NDP-α-MSH, both in the heart and liver. These results indicate that melanocortins inhibit heart and liver damage triggered by prolonged myocardial ischemia/reperfusion likely, as main mechanism, via the vagus nerve-mediated modulation of the JAK/STAT/ERK signaling pathways.

• Authors: Alessandra Ottani, Daniela Giuliani, Laura Neri, Anita Calevro, Fabrizio Canalini, Eleonora Vandini, Maria Michela Cainazzo, Ippazio Antonio Ruberto, Alberto Barbieri, Rosario Rossi, Salvatore Guarini
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 769 Pg. 22-32 (Dec 15 2015) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 26477637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Cardiotonic Agents
• STAT3 Transcription Factor
• alpha-MSH
• MSH, 4-Nle-7-Phe-alpha-
• Janus Kinases
• Extracellular Signal-Regulated MAP Kinases
• Acetylcholine

Topics

• Acetylcholine (metabolism)
• Animals
• Apoptosis (drug effects)
• Blood Pressure (drug effects)
• Cardiotonic Agents (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Heart (drug effects, physiopathology)
• Janus Kinases (metabolism)
• Liver (drug effects, pathology, physiopathology)
• Male
• Myocardial Reperfusion Injury (pathology, physiopathology, prevention & control)
• Myocardium (pathology)
• Rats
• Rats, Wistar
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Vagus Nerve (drug effects)
• alpha-MSH (analogs & derivatives, pharmacology)