Augmented Expression of Cardiotrophin-1 in Failing Human Hearts Is Accompanied by Diminished Glycoprotein 130 Receptor Protein Abundance

Zolk, Oliver; Ng, Leong L.; O’Brien, Russell J.; Weyand, Michael; Eschenhagen, Thomas

doi:10.1161/01.cir.0000033117.39335.df

Cited by 90 publications

(65 citation statements)

References 15 publications

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“…■ 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: 99%

Section: General Overview On Gp130 Signalingmentioning

confidence: 99%

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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“…Further study showed that CT-1 caused both enhanced survival and hypertrophy of differentiated cardiac muscle cells and inhibited cardiac myocyte apoptosis after serum deprivation or cytokine stimulation (25,30,36,37,40). CT-1, acting through the gp130 receptor common to the IL-6 family, has been reported to be critical in the induction of hypertrophy in response to biomechanical overload and is overexpressed in cardiomyopathy, as part of a panel of "fetal" genes induced in response to damage (14,28).…”

mentioning

confidence: 99%

Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants

Zheng

Zhou

Seow

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants. Am J Physiol Lung Cell Mol Physiol 287: L1165-L1171, 2004. First published July 23, 2004 doi:10.1152/ ajplung.00171.2004.-Induction of hypertrophy and inhibition of apoptosis may be important mechanisms contributing to increased airway smooth muscle (ASM) mass in asthma. Data from our laboratory indicate that cardiotrophin-1 (CT-1) induces hypertrophy and inhibits apoptosis in isolated human ASM cells. To determine whether these novel effects of CT-1 also occur in the airway tissue milieu and to determine whether structural changes are accompanied by functional changes, matched pairs of guinea pig airway explants were treated with or without CT-1 for 7 days, and structural features as well as isometric and isotonic contractile and relaxant mechanical properties were measured. CT-1 (0.2-5 ng/ml) increased both myocyte mass and extracellular matrix in a concentration-dependent fashion. CT-1 (10 ng/ml)-treated tissues exhibited a significant increase in passive tension at all lengths on day 7; at optimal length, passive tension generated by CT-1-treated tissues was 1.72 Ϯ 0.12 vs. 1.0 Ϯ 0.1 g for control. Maximal isometric stress was decreased in the CT-1-treated group on day 7 (0.39 Ϯ 0.10 kg/cm 2 ) vs. control (0.77 Ϯ 0.15 kg/cm 2 , P Ͻ 0.05). Isoproterenol-induced relaxant potency was reduced in CT-1-treated tissues, log EC50 being Ϫ7.28 Ϯ 0.34 vs. Ϫ8.12 Ϯ 0.25 M in control, P Ͻ 0.05. These data indicate that CT-1 alters ASM structural and mechanical properties in the tissue environment and suggest that structural changes found in the airway wall in asthma are not necessarily associated with increased responsiveness. tracheal explants; mechanics; cytokines; asthma; matrix; smooth muscle hypertrophy INCREASED SMOOTH MUSCLE MASS has been repeatedly documented in asthmatic subjects (3,11,29,33,34), but the mechanisms responsible for the increased mass are unclear. The amount of both airway smooth muscle (ASM) and smooth muscle-associated matrix is greater with increased duration of asthma and may be an important determinant of the severity of airway responsiveness (3,15). Yet the functional alterations in ASM in asthma are uncertain (29, 34). When bronchial segments from asthmatics have been studied in vitro, the majority of studies have shown no change in mechanical properties, although isolated cells from asthmatics show a higher velocity of shortening (16). Tracheal tissue offers some advantages in studies of ASM behavior in that the muscle is more uniform in orientation, and less matrix elements are present. The only study of asthmatic trachea, in severe asthma, showed a nonspecific increase in force generation, suggesting increased contractility. However, force was normalized to tissue weight, not muscle mass (1); thus, the changes could have been a reflection of increased muscle.Cardiotrophin-1 (CT-1), a member of the IL-6 family, was initially defined as a factor that has the capacity to induce cardiac myocyt...

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Augmented Expression of Cardiotrophin-1 in Failing Human Hearts Is Accompanied by Diminished Glycoprotein 130 Receptor Protein Abundance

Cited by 90 publications

References 15 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

Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants

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