Modulation of the JAK/ERK/STAT signaling in melanocortin-induced inhibition of local and systemic responses to myocardial ischemia/reperfusion

• Published in: Pharmacological research 2013-06, Vol.72, p.1-8
• Main Authors: Ottani, Alessandra, Galantucci, Maria, Ardimento, Ettore, Neri, Laura, Canalini, Fabrizio, Calevro, Anita, Zaffe, Davide, Novellino, Ettore, Grieco, Paolo, Giuliani, Daniela, Guarini, Salvatore
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Extracellular Signal-Regulated MAP Kinases - metabolism; Heart - drug effects; Heart - physiopathology; Inhibition of local and systemic responses; JAK/ERK/STAT signaling; Janus Kinases - metabolism; Male; Melanocortins; Melanocortins - therapeutic use; Myocardial Ischemia - drug therapy; Myocardial Ischemia - metabolism; Myocardial Ischemia - physiopathology; Myocardial ischemia/reperfusion; Myocardial Reperfusion - methods; Myocardium - metabolism; Myocardium - pathology; Rats; Rats, Wistar; Signal Transduction - drug effects; STAT Transcription Factors - metabolism
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2013.03.005

The janus kinases (JAK), extracellular signal-regulated kinases (ERK) and signal transducers and activators of transcription (STAT) pathways have been shown to play a cardioprotective role. We previously gave evidence that melanocortins afford cardioprotection in conditions of myocardial ischemia/reperfusion. Here we aimed to investigate the influence of melanocortins on the JAK/ERK/STAT signaling in cardiac and systemic responses to prolonged myocardial ischemia/reperfusion. Ischemia was produced in rats by ligature of the left anterior descending coronary artery for 30min. At the end of the 2-h reperfusion, western blot analysis of the cardioprotective transcription factors pJAK2, pERK1/2, pTyr-STAT3 and pSer-STAT3, the inflammatory mediator tumor necrosis factor-α (TNF-α), the pro-apoptotic factors BAX and c-jun N-terminal kinases (pJNK), the anti-apoptotic protein Bcl-XL, as well as of the cardioprotective enzyme heme oxygenase-1 (HO-1), was performed in the left ventricle and spleen. Intravenous treatment, during coronary artery occlusion, with the melanocortin analogs [Nle4, D-Phe7]α-melanocyte-stimulating hormone (NDP-α-MSH) and adrenocorticotropic hormone 1-24 [ACTH-(1-24)], induced a left ventricle up-regulation of pJAK2, pERK1/2 and pTyr-STAT3 (JAK-dependent), and a reduction in pJNK and TNF-α levels; these effects of NDP-α-MSH and ACTH-(1-24) were associated with over-expression of the pro-survival proteins HO-1 and Bcl-XL, and marked decrease of the myocardial infarct size. Melanocortin treatment did not affect left ventricle pSer-STAT3 (ERK1/2-dependent) and BAX levels. In the spleen, NDP-α-MSH and ACTH-(1-24) induced similar effects on the expression of the above transcription factors/proteins, except for pERK1/2 (down-regulated) and HO-1 (unaffected). Blockade of JAK and ERK pathways with AG490 and U0126, respectively, abrogated the myocardial infarct size reduction by NDP-α-MSH. These results indicate that melanocortins inhibit local and systemic inflammatory and apoptotic cascades triggered by prolonged myocardial ischemia/reperfusion, with consequent reduction in myocardium infarct size, seemingly via activation of the JAK/STAT signaling and with modulation of an ERK (STAT unrelated) signaling pathway.