Modulation of the JAK/ERK/STAT signaling in melanocortin-induced inhibition of local and systemic responses to myocardial ischemia/reperfusion.
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 [Nle(4), D-Phe(7)]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.
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CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-N GENE-N GENE-N GENE-Y GENE-Y GENE-N GENE-N GENE-N GENE-N GENE-Y GENE-N GENE-Y GENE-N GENE-N GENE-N GENE-N GENE-N GENE-Y GENE-N GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-N GENE-Y
Nle D-Phe AG490 U0126 N melanocortin α-melanocyte-stimulating hormone α-MSH adrenocorticotropic hormone 1-24 ACTH-(1-24) pJAK2 pERK1/2 STAT pTyr-STAT3 JAK pJNK TNF-α α-MSH ACTH-(1-24) HO-1 Bcl-XL Melanocortin pSer-STAT3 ERK1/2 BAX α-MSH ACTH-(1-24) pERK1/2 HO-1 JAK ERK JAK α-MSH melanocortins JAK STAT ERK STAT melanocortins extracellular signal-regulated kinases melanocortins JAK ERK STAT janus kinases ERK pJAK2 pERK1/2 pTyr-STAT3 pSer-STAT3 signal transducers and activators of transcription tumor necrosis factor-α TNF-α BAX c-jun N-terminal kinases pJNK Bcl-XL heme oxygenase-1 HO-1 JAK ERK STAT melanocortin