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

Melanocortin peptides afford cardioprotection during myocardial ischemia/reperfusion via janus kinases OAK), 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 30 min; effects of ischemia/reperfusion were evaluated using Western blot of heart and liver proteins. Intravenous treatment, during coronary artery occlusion, with the melanocortin analog (NIe(4), D-Phe(7))alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) induced a left ventricle up-regulation of the cardioprotective transcription factors pJAK2, pERK1/2 and pTyrSTAT3 OAK-dependent), and a reduction in the levels of the inflammatory mediators tumor necrosis factor-alpha (TNF-alpha) and pINK (a transcription factor also involved in apoptosis), as assessed at the end of the 2-h reperfusion period. Further, these beneficial effects of NDP-alpha-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-alpha-MSH induced a decrease in the pJAK2 and pTyr-STAT3 levels, and strongly reduced pERK1/2 expression. In the liver of ischemic rats NDP-alpha-MSH also blunted pINK activity and TNIF-oc expression, and up-regulated Bcl-xL. Bilateral cervical vagotomy prevented all effects of NDP-alpha-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. (C) 2015 Elsevier B.V. All rights reserved.