Alterations in Janus Kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) Signaling in Patients With End-Stage Dilated Cardiomyopathy

Podewski, Edith; Hilfiker‐Kleiner, Denise; Hilfiker, Andres; Morawietz, Henning; Lichtenberg, Artur; Wollert, Kai C.; Drexler, Helmut

doi:10.1161/01.cir.0000057545.82749.ff

Cited by 135 publications

(116 citation statements)

References 22 publications

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“…Not much information is available to date on the expression state of SOCS proteins, negative regulators of gp130-JAK/STAT signaling, in human failing hearts. One report shows that terminally failing human hearts display increased SOCS-1 and reduced SOCS-3 protein levels [113]. Taken together, circulating IL-6 cytokines positively correlate with the progression of heart failure and the local IL-6-gp130-STAT3 signaling cascade in human failing hearts is dysregulated at all levels.…”

Section: General Overview On Gp130 Signalingmentioning

confidence: 95%

“…■ Changes in myocardial expression of the IL-6 type family of cytokines Intriguingly, not only systemic levels of IL-6 type cytokines and sgp130 are elevated in cardiovascular disease but also the local gp130-STAT3 signaling cascade is altered at every level in the failing human heart [28, 67,68,113,175]. For instance, it is known that both CT-1 and LIF are increasingly expressed in the failing left ventricular myocardium.…”

Section: General Overview On Gp130 Signalingmentioning

confidence: 99%

“…On the other hand myocardial levels of IL-6 and LIF receptor appear to be reduced in patients with dilative cardiomyopathy [28,67]. Interestingly, while the gp130 receptor was found to be hyperphosphorylated [113], gp130 protein expression is not altered [113] or even diminished in the failing left ventricular myocardium [175]. Expression and phosphorylation levels of STAT3 [52,113], the major downstream signaling molecule of IL-6, as well as phosphorylation of its upstream activators JAK2 and TYK1 is severely reduced in failing hearts of different etiology [113].…”

Section: General Overview On Gp130 Signalingmentioning

confidence: 99%

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Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis

2007

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■ Abstract Circulating levels of interleukin (IL)-6 and related cytokines are elevated in patients with congestive heart failure and after myocardial infarction. Serum IL-6 concentrations are related to decreasing functional status of these patients and provide important prognostic information. Moreover, in the failing human heart, multiple components of the IL-6-glycoprotein (gp)130 receptor system are impaired, implicating an important role of this system in cardiac pathophysiology.Experimental studies have shown that the common receptor subunit of IL-6 cytokines is phosphorylated in response to pressure overload and myocardial infarction and that it subsequently activates at least three different downstream signaling pathways, the signal transducers and activators of transcription 1 and 3 (STAT1/3), the Src-homology tyrosine phosphatase 2 (SHP2)-Ras-ERK, and the PI3K-Akt system. Gp130 receptor mediated signaling promotes cardiomyocyte survival, induces hypertrophy, modulates cardiac extracellular matrix and cardiac function. In this regard, the gp130 receptor system and its main downstream mediator STAT3 play a key role in cardioprotection.This review summarizes the current knowledge of IL-6 cytokines, gp130 receptor and STAT3 signaling in the heart exposed to physiological (aging, pregnancy) and pathophysiological stress (ischemia, pressure overload, inflammation and cardiotoxic agents) with a special focus on the potential role of individual IL-6 cytokines.

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Section: General Overview On Gp130 Signalingmentioning

confidence: 95%

Section: General Overview On Gp130 Signalingmentioning

confidence: 99%

Section: General Overview On Gp130 Signalingmentioning

confidence: 99%

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Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis

2007

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“…Although the ligand-binding IL-6R alone is not capable of signal transduction, the signaling component gp130 is also involved in the transduction of signals from other ligands of the IL-6 family. When IL-6 is induced by sustained β-adrenoceptor activation, the capacity for signal transduction by IL-6 is probably maintained, because: (a) we found no lowering in the myocardial mRNA expression of IL-6R or gp130 in any model with sustained β-adrenergic activation; (b) in cardiomyocytes, isoproterenol causes a delayed activation of STAT3 (a hallmark of gp130-dependent signal transduction), which can be attenuated by an IL-6-neutralizing antibody (6); and (c) in failing human myocardium, other studies have demonstrated phosphorylation of gp130 and of downstream signaling components (STAT1, STAT3) (24,25).…”

Section: Relevance Of β-Adrenoceptor-mediatedmentioning

confidence: 99%

Activation of AP-1 Contributes to the β-Adrenoceptor-Mediated Myocardial Induction of Interleukin-6

Rohrbach

Engelhardt

Werdan

et al. 2007

Mol Med

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The induction of proinflammatory cytokines in stressed myocardium is considered an innate immune response, but the role of β-adrenergic signaling in this proinflammatory response and the mechanisms of cardioprotection by β-blockers are not fully understood. In the present study, we analyzed interleukin-6 (IL-6) formation and promoter activation in β-adrenoceptor-stimulated neonatal rat cardiomyocytes, in transgenic mice with cardiac overexpression of β1-adrenoceptors, and in failing human myocardium. IL-6 formation and release in cultured cardiomyocytes under β-adrenoceptor stimulation requires the activation of activating protein-1 (AP-1) binding sites and of cAMP response elements (CRE) in the IL-6 promoter, but this release (140 ± 6 pg/mL medium under 10 -6 M isoproterenol vs. 81 ± 3 pg/mL unstimulated, P < 0.05) is moderate compared with that under inflammatory stimulation (855 ± 44 pg/mL, endotoxin 0.1µg/mL). Similarly, IL-6 is induced together with CRE-and AP-1 activation in the left ventricle (LV) of β1-transgenic mice before the onset of failure. However, we observed IL-6 induction with activation of NF-κB in addition to CRE and AP-1 in β1-transgenic mice at the age of 22 weeks and in explanted human LV after full development of failure. Treatment with β-blockers lowered myocardial IL-6 as well as AP-1, NF-κB, and CRE activation. Therefore, the activation of AP-1 and CRE is part of β-adrenergic signal transduction for IL-6 induction in nonfailing and failing cardiomyocytes, whereas NF-κB activation contributes only in overloaded failing myocardium.

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“…STAT3 in particular mediates a signal transduction that promotes cellular growth and reverses apoptosis, and thus plays a key role in neovascularization and cellular survival. Studies have shown that deletion of STAT3 in mice causes cardiomyopathy (14), and in patients with the disease, the level of STAT3 in the myocardia was significantly low (15). All these suggest that activating the JAK/STAT3 pathway may be the key to preventing the onset of heart failure.…”

Section: Discussionmentioning

confidence: 98%

The cardioprotective effect of interleukin-11 against ischemia-reperfusion injury in a heart donor model

Tamura¹,

Kohno²,

Mohri³

et al. 2018

Ann. Cardiothorac. Surg.

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Background: Previously, we have demonstrated the cardioprotective effect of interleukin (IL)-11 in animal models of acute coronary syndrome. In this study, we sought to evaluate its cardioprotective potential during prolonged hypothermic global ischemia and subsequent reperfusion using a rat heart donor model.Methods: IL-11 was administered intravenously 10 minutes before harvesting the rat heart. The hearts were preserved in cold (4 ℃) Krebs-Henseleit buffer for 6 hours, and then attached to a Langendorff perfusion apparatus and reperfused with an oxygenated Krebs-Henseleit solution containing IL-11.Normal saline was used instead of IL-11 in the control group. Functional recovery of the reperfused heart was observed by using a left ventricular balloon. Myocardial cell injury was quantified by measuring the biomarkers collected from the coronary effluent. Apoptotic cells were identified and counted using the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) staining technique.Results: IL-11 administration improved myocardial function after 6 hours of cold ischemia. Although there were no significant differences in any of the baseline-measured values between the two groups, left ventricular developed pressure (LVDP) and changes in left ventricular pressures (dP/dt) were significantly higher in the IL-11 group at 120-minute reperfusion. The number of TUNEL-labeled cardiomyocytes was also significantly smaller in the IL-11 group. Conclusions:The administration of IL-11 showed a significant recovery of cardiac contractile function after 6 hours of cold ischemia. Our data suggest that it may have significant therapeutic potential for maintaining the functional viability of the heart exposed to prolonged hypothermic global ischemia.

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Alterations in Janus Kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) Signaling in Patients With End-Stage Dilated Cardiomyopathy

Cited by 135 publications

References 22 publications

Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis

Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis

Activation of AP-1 Contributes to the β-Adrenoceptor-Mediated Myocardial Induction of Interleukin-6

The cardioprotective effect of interleukin-11 against ischemia-reperfusion injury in a heart donor model

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