Activation of JAK-STAT and MAP Kinases by Leukemia Inhibitory Factor Through gp130 in Cardiac Myocytes

Kunisada, Keita; Hirota, Hisao; Fujio, Yasushi; Matsui, Hideo; Tani, Yoshihiko; Yamauchi–Takihara, Keiko; Kishimoto, Tadamitsu

doi:10.1161/01.cir.94.10.2626

Cited by 172 publications

(122 citation statements)

References 36 publications

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“…Evidence for JAK/STAT signaling in the heart originally came from studies conducted with rat cardiac myocytes, treatment with leukemia inhibitory factor being found to result in STAT3 activation (18). Subsequently, STAT1 and STAT3 activation was shown to occur in the heart following pressure overload-induced hypertrophy (23).…”

Section: Discussionmentioning

confidence: 99%

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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%

“…It is active in various organs and tissues and has been implicated in cardiac hypertrophy (18,23) and cardiomyocyte apoptosis (28). More recently, evidence has been presented indicating that, in addition to the PI3K-Akt and p44/42 pathways, the JAK/STAT pathway may also play an important role in the protection against myocardial I/R injury (3)(4)(5)26).…”

mentioning

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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“…Primary cultures of neonatal cardiac myocytes were prepared by collagenase and trypsin digestion from the ventricles of 1-d-old Sprague Dawley rats, or 1-2-d-old DDY mice, obtained from Nippon Dobutsu (Osaka, Japan) as described previously (14). In brief, cultures were enriched with cardiac myocytes by preplating for 60 min to deplete the population of nonmyocardial cells (NMC).…”

Section: Methodsmentioning

confidence: 99%

Signals through gp130 upregulate bcl-x gene expression via STAT1-binding cis-element in cardiac myocytes.

Fujio

Kunisada²,

Hirota³

et al. 1997

J. Clin. Invest.

186

123

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We described recently the activation of the Janus kinasesignal transducer and activator of transcription (Jak-STAT) and mitogen-activated protein (MAP) kinase pathways by leukemia inhibitory factor (LIF) through gp130, a signal transducer of IL-6-related cytokines, that transduces hypertrophic signals in cardiac myocytes. In addition, stimulation of gp130 by IL-6-related cytokines is known to exert a cytoprotective effect.In the present study, we investigated the possibility that activation of gp130 initiates activation of the cytoprotective genes in cardiac myocytes. Incubation of cardiac myocytes with LIF induced the expression of bcl-x, and the isoform that was induced by LIF was identified as bcl-xL. Induction of bcl-xL protein was also identified by Western blotting. Antisense oligonucleotide against bcl-x mRNA inhibited protective effect of LIF accompanied with the reduction in bclxL protein.We constructed bcl-x promoter-luciferase reporter gene plasmids ( Ϫ 639/ ϩ 10-or Ϫ 161/ ϩ 10-luciferase), and transfected them to cardiac myocytes. LIF stimulation increased the luciferase activity of Ϫ 639/ ϩ 10-luciferase plasmids. Although Ϫ 161/ ϩ 10-luciferase plasmids presented comparable responsiveness to LIF, the basal transcription level was impaired. The LIF-responsive cis -element was localized to a DNA fragment (positions Ϫ 161 to ϩ 10) that contains an interferon-␥ activation site (GAS) motif (TTCGGAGAA) at position Ϫ 41 of the bcl-x gene promoter. This motif bound to STAT1, not to STAT3, and site-directed mutagenesis revealed that this motif was essential for LIF-responsive promoter activity.These data suggest that LIF induces bcl-x mRNA via STAT1 binding cis -element in cardiac myocytes, presenting cytoprotective effect. ( J. Clin. Invest. 1997. 99:2898-2905.)

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“…The stimulation of GP130 activates Janus kinase/STAT, mitogen activated protein kinase, and phosphatidylinositol 3-kinase/Akt pathways (11,12). The signals through GP130 transduce cell survival signals as well as hypertrophic signals (13)(14)(15)(16).…”

mentioning

confidence: 99%

Cardiac-specific Activation of Signal Transducer and Activator of Transcription 3 Promotes Vascular Formation in the Heart

Osugi

Oshima

Fujio

et al. 2002

Journal of Biological Chemistry

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141

101

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Signal transducer and activator of transcription 3 (STAT3) functions in cell proliferation, differentiation, and cell survival. Previously, we have demonstrated that the activation of STAT3 is required for glycoprotein 130-mediated induction of VEGF in cardiac myocytes, but the functional importance of STAT3 as an angiogenic mediator remains to be determined. To address this issue, we first generated the adenoviral vector expressing constitutively active STAT3 (caSTAT3). Adenoviral gene transfer of caSTAT3 induced an increase in the expression of VEGF in cultured cardiomyocytes. The conditioned medium from caSTAT3-transfected cardiomyocyte culture promoted endothelial tubule formation, which was inhibited by anti-VEGF antibody. Next, we generated the transgenic (TG) mice with cardiacspecific overexpression of caSTAT3 and demonstrated that caSTAT3 TG mice showed evidence of VEGF induction in the hearts. The caSTAT3 TG hearts also demonstrated increased capillary density accompanied by an increase in the expression of VE-cadherin, an endothelial-specific component. These data indicate that caSTAT3 TG hearts exhibit an enriched vascular structure compared with non-transgenic hearts. The study presented here provides the first evidence that activation of STAT3 controls vessel growth in vivo and suggests that STAT3 contributes to cardiac adaptation by regulating vascular function under the conditions of stress.

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Activation of JAK-STAT and MAP Kinases by Leukemia Inhibitory Factor Through gp130 in Cardiac Myocytes

Abstract: These results demonstrate for the first time that a JAK-STAT pathway and a MAPK pathway are present down-stream of gp130 in cardiac myocytes and are rapidly activated by LIF both in vitro and in vivo. Activation of gp130 constitutes a novel signaling pathway in cardiac myocytes.

Cited by 172 publications

References 36 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

Signals through gp130 upregulate bcl-x gene expression via STAT1-binding cis-element in cardiac myocytes.

Cardiac-specific Activation of Signal Transducer and Activator of Transcription 3 Promotes Vascular Formation in the Heart

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