Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion

Fuglesteg, Britt N.; Suleman, Naushaad; Tiron, Crina; Kanhema, Tambuzai; Lacerda, Lydia; Andreasen, Thomas V.; Sack, Michael N.; Jonassen, Anne K.; Mjøs, Ole D.; Opie, Lionel H.; Lecour, Sandrine

doi:10.1007/s00395-008-0728-x

Cited by 85 publications

(61 citation statements)

References 53 publications

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“…Indeed, it has been proposed that JAK/STAT activation, stimulated by postconditioning, may precede Akt phosphorylation and that JAK/ STAT phosphorylation in the absence of RISK activation is insufficient to provide protection (12). More recently, cardioprotection induced by insulin was suggested to involve a close interaction between STAT3 and Akt (11). This area of investigation is, however, still in its early stages, and whether JAK-STAT signaling operates upstream of the RISK pathway, in relation to cardioprotection, or the two pathways operate in parallel remains to be established definitively.…”

Section: Discussionmentioning

confidence: 99%

Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore

Smith

Dixon

Wynne

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

100

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Smith CC, Dixon RA, Wynne AM, Theodorou L, Ong SG, Subrayan S, Davidson SM, Hausenloy DJ, Yellon DM. Leptininduced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore. Am J Physiol Heart Circ Physiol 299: H1265-H1270, 2010. First published July 23, 2010; doi:10.1152/ajpheart.00092.2010.-Leptin-induced protection against myocardial ischemia-reperfusion (I/R) injury involves the activation of the reperfusion injury salvage kinase pathway, incorporating phosphatidylinositol 3-kinase-Akt/protein kinase B and p44/42 MAPK, and the inhibition of the mitochondrial permeability transition pore (MPTP). Recently published data indicate that the JAK/STAT signaling pathway, which mediates the metabolic actions of leptin, also plays a pivotal role in cardioprotection. Consequently, in the present study we considered the possibility that JAK/STAT signaling linked to the MPTP may be involved in modulating the cardioprotective actions of leptin. Employing rat in vitro models (Langendorffperfused hearts and cardiomyocytes) of I/R injury, we investigated the actions of leptin (10 nM), administered at reperfusion, in the presence or absence of the JAK2 inhibitor, AG-490 (5 M). Leptin reduced infarct size significantly (control, 60.05 Ϯ 7.41% vs. leptin treated, 29.9 Ϯ 3.24%, P Ͻ 0.05), protection being abolished by AG-490. Time course studies revealed that leptin caused a 171% (P Ͻ 0.001) increase in STAT3/tyrosine-705 phosphorylation at 2.5 min reperfusion; however, increases were not seen at 5, 10, 15, or 30 min reperfusion. Contrasting with STAT3, Akt/serine-473 phosphorylation was not significantly increased until 15 min into the reperfusion phase (140%, P Ͻ 0.05). AG-490 blocked the leptin-induced rise in STAT3 phosphorylation seen at 2.5 min reperfusion but did not influence Akt/serine-473 phosphorylation at 15 min. Leptin reduced the MPTP opening (P Ͻ 0.001), which was blocked by AG-490. This is the first study to yield evidence that JAK/STAT signaling linked to the MPTP plays a role in leptin-induced cardioprotection. Under the experimental conditions employed, STAT3 phosphorylation appears to have occurred earlier during reperfusion than that of Akt. Further research into the interactions between these two signaling pathways in the setting of I/R injury is, however, required. myocardium; ischemia-reperfusion injury; Janus-activated kinase/signal transducer and activator of transcription signaling

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Section: Discussionmentioning

confidence: 99%

Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore

Smith

Dixon

Wynne

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

100

View full text Add to dashboard Cite

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“…22 Sphingosine kinase-1, the key enzyme that catalyzes the formation of sphingosine-1-phosphate, is also important for postconditioning in mice, 23 and sphingosine kinase activation is probably mediated by STAT3. 24 Whereas the present study revealed major differences in signal transduction by RISK between rodents and pigs, both sphingosine 25 and STAT3 26 are parts of the signal transduction of tumor necrosis factor (TNF)␣-induced cardioprotection, TNF␣-induced cardioprotection does not rely on AKT and ERK1/2, 26 and TNF␣ is also cardioprotective in pigs.…”

Section: Discussionmentioning

confidence: 99%

Ischemic Postconditioning in Pigs

Skyschally

Caster

Boengler

et al. 2009

Circulation Research

238

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I schemic postconditioning (IPoC) reduces infarct size by attenuation of reperfusion injury 1 and is operative in all species studied so far, including humans. 2,3 The phosphorylation of RISK (reperfusion injury salvage kinases), ie, phosphatidylinositol 3-kinase/protein kinase B (PI3K-AKT), 4,5 mitogen-activated protein kinase kinase/extracellular signal regulated kinase (ERK) (MEK1/2-ERK1/2), 6 p70 ribosomal S6 protein kinase (P70S6K), and glycogen synthase kinase (GSK)3␤ was proposed to be causal for protection by IPoC. 4 -7 Activation of sarcolemmal receptors projects through parallel pathways of either PI3K-AKT or MEK1/2-ERK1/2 onto P70S6K and ultimately on GSK3␤, which, when phosphorylated, inhibits mitochondrial permeability transition pore opening. 8 Whether specific RISK kinases or a concert of different RISK kinases confer the protection by postconditioning is less clear. 4,6,7,9,10 In 2 studies, there was RISK phosphorylation but no protection by postconditioning. 11,12 Most studies on the role of RISK in postconditioning were performed in rodent hearts, 4,6,7 which, apart from species differences to larger mammals including humans, may pose methodological limitations: the small amount of tissue available for Western blots permits neither determination of baseline values nor that of infarct size in an individual heart. The association of RISK phosphorylation with less infarction could therefore be cause or consequence of the observed protection.The present study evaluates the role of RISK for postconditioning in pigs. With regard to size, coronary anatomy, and heart rate, the pig heart resembles more closely the human heart than smaller species, and it permits taking multiple biopsies at different time points and determining infarct size in an individual heart. Materials and MethodsThe experiments were performed in an established pig model of regional ischemia/reperfusion with infarct size determination and Western blot analysis (see the expanded Materials and Methods section in the online data supplement, available at http://circres. ahajournals.org). Protocol 1IPoC (nϭ13) was induced by 6 cycles of 20 seconds of reperfusion and 20 seconds of reocclusion at the onset of reperfusion. Immediate full reperfusion (IFR) (nϭ15) was established for comparison. Protocol 2In 8 animals, 4 with IPoC (B-IPoC) and 4 with IFR (B-IFR), the 2 major upstream RISK pathways PI3K-AKT and MEK1/2-ERK1/2 were blocked before the onset of reperfusion (see the online data supplement). StatisticsData are meansϮSEM. Data were analyzed by 2-way ANOVA for repeated measures with least significant difference tests or doublesided t tests; PϽ0.05 was considered significant.

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“…The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways are responsive to a large number of cytokines, growth factors and hormones and play a vital role in mediating cardioprotection from IR injuries [5,17,22]. Experimental evidence indicates that the JAK2/STAT3 signaling pathway is specifically involved in preventing myocardial IR injury [21,25].…”

Section: Introductionmentioning

confidence: 99%

The effects of curcumin post-treatment against myocardial ischemia and reperfusion by activation of the JAK2/STAT3 signaling pathway

et al. 2012

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In this study, we evaluated the effect of curcumin (Cur) post-treatment on isolated perfused rat hearts that had been subjected to a protocol of ischemia and reperfusion injury. We also examined whether the Janus kinase 2 and signal transducer and activator 3 of transcription (JAK2/STAT3) signaling pathway plays a role in the cardioprotective effects of Cur post-treatment. Isolated perfused rat hearts were subjected to 60 min of ischemia, followed by 60 min of reperfusion. The hearts were exposed to 1-μM Cur during the first 10 min of reperfusion in the absence or presence of the JAK kinase-specific inhibitor AG490 (AG, 1 μM). The Cur treatment conferred a cardioprotective effect, and the treated hearts demonstrated an improved post-ischemic cardiac functional recovery, a decreased myocardial infarct size and decreased lactate dehydrogenase release in the coronary flow, a reduced number of apoptotic cardiomyocytes, up-regulation of the anti-apoptotic protein Bcl2 and down-regulation of the pro-apoptotic protein Caspase3. AG blocked the Cur-mediated cardioprotection by inhibiting the JAK2/STAT3 signaling pathway, as reflected by the abrogation of the Cur-induced up-regulation of Bcl2 and down-regulation of Caspase3. The results suggest that Cur post-treatment can attenuate IR injury through the activation of the JAK2/STAT3 signaling pathway, which transmits a survival signal to the myocardium.

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Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion

Cited by 85 publications

References 53 publications

Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore

Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore

Ischemic Postconditioning in Pigs

The effects of curcumin post-treatment against myocardial ischemia and reperfusion by activation of the JAK2/STAT3 signaling pathway

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