title: 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.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ottani
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Neri
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Calevro
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Canalini
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Vandini
authors.affiliation: Division of Toxicology and Clinical Pharmacology, University of Modena and Reggio Emilia, Modena Italy.
authors.forename: Maria Michela
authors.initials: MM
authors.lastname: Cainazzo
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Ippazio Antonio
authors.initials: IA
authors.lastname: Ruberto
authors.affiliation: Division (School) of Anesthesia and Intensive Care, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Barbieri
authors.affiliation: Division of Cardiology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Rossi
authors.affiliation: Department of Biomedical, Metabolic and Neural Sciences, Section of Pharmacology and Molecular Medicine, University of Modena and Reggio Emilia, Modena, Italy. Electronic address: salvatore.guarini@unimore.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D053612:Janus Kinases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014630:Vagus Nerve / Q000187:drug effects*; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D050796:STAT3 Transcription Factor; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D053612:Janus Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000109:Acetylcholine
keywords: Inhibition of local and systemic responses; JAK/ERK/STAT signaling; Liver; Melanocortins; Myocardial ischemia/reperfusion; NDP-alpha-MSH (PubChem CID: 44277697); Vagus nerve