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

Fischer, Philipp; Hilfiker‐Kleiner, Denise

doi:10.1007/s00395-007-0674-z

Cited by 184 publications

(99 citation statements)

References 170 publications

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“…IL-6 is a pleiotropic cytokine that induces multiple signals in different target cells (26) and has varying effects on myocardial function [recent review in (27)]. In mammalian cardiomyocytes, IL-6 signaling combines inflammatory activation with antiapoptotic survival pathway activation (28), preventing decompensation during cardiac overload (29).…”

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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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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“…Upon activation of JAK, STAT proteins dimerize and translocate to the nucleus, where they mediate gene transcription (reviewed by Sandberg et al [36]). In myocardial tissue it can be difficult to distinguish which receptor system is responsible for activation of JAK/STAT signalling [12]. Previous reports have shown that administrating insulin at reperfusion following ischemia/reperfusion induces cardioprotection via activation of a cascade of prosurvival protein kinases, including phosphatidylinositol 3-kinase (PI3K), Akt and p70s6 kinase [19,20].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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Objective-To evaluate the significance of the JAK-STAT pathway in insulin-induced cardioprotection from reperfusion injury. Correspondence to: Britt N. Fuglesteg, brittf@fagmed.uit.no Methods-In isolated perfused rat hearts subjected to insulin therapy (0.3 mU/ml) ± AG490 (5 μM, JAK-STAT inhibitor), the phosphorylation state of STAT3 and Akt was determined after 15 min of reperfusion. Infarct size was measured after 120 min of reperfusion. Isolated cardiac myocytes from wild type (WT) and cardiac specific STAT3 deficient mice were treated with insulin at reoxygenation following simulated ischemia (SI, 26 h). Cell viability was measured after 120 min of reoxygenation following SI, whereas phosphorylation state of Akt was measured after 15 min of reoxygenation following SI.Results-Insulin given at reperfusion led to phosphorylation of STAT3 and Akt both of which were inhibited by AG490. AG490 also blocked the insulin-dependent decrease in infarct size, supporting a role for JAK-STAT in cardioprotection. In addition, insulin protection from SI was blocked in myocytes from the STAT3 deficient mice, or in WT mice treated with AG490. Furthermore, insulin failed to phosphorylate Akt in the STAT3 deficient cardiomyocytes.Conclusion-Insulin-induced cardioprotection at reperfusion occurs through activation of STAT3. Inhibiting STAT3 by AG490, or STAT3 depletion in cardiac myocytes affects activation of Akt, suggesting close interaction between STAT3 and Akt in the cardioprotective signalling pathway activated by insulin treatment at reperfusion.

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“…The IL-6 family of cytokines mostly activates STAT3 and to a lesser extent STAT1 via a common receptor subunit (13). STAT proteins are also shown to be activated by interleukins indirectly through the activation of mitogen-activated protein kinases (MAPKs).…”

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confidence: 99%

Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) Attenuates Interleukin-6 (IL-6)-induced Collagen Synthesis and Resultant Hypertrophy in Rat Heart

Mir

Chatterjee

Mitra

et al. 2012

Journal of Biological Chemistry

125

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IL-6 has been shown to play a major role in collagen up-regulation process during cardiac hypertrophy, although the precise mechanism is still not known. In this study we have analyzed the mechanism by which IL-6 modulates cardiac hypertrophy. For the in vitro model, IL-6-treated cultured cardiac fibroblasts were used, whereas the in vivo cardiac hypertrophy model was generated by renal artery ligation in adult male Wistar rats (Rattus norvegicus). During induction of hypertrophy, increased phosphorylation of STAT1, STAT3, MAPK, and ERK proteins was observed both in vitro and in vivo. Treatment of fibroblasts with specific inhibitors for STAT1 (fludarabine, 50 M), STAT3 (S31-201, 10 M), p38 MAPK (SB203580, 10 M), and ERK1/2 (U0126, 10 M) resulted in down-regulation of IL-6-induced phosphorylation of specific proteins; however, only S31-201 and SB203580 inhibited collagen biosynthesis. In ligated rats in vivo, only STAT3 inhibitors resulted in significant decrease in collagen synthesis and hypertrophy markers such as atrial natriuretic factor and ␤-myosin heavy chain. In addition, decreased heart weight to body weight ratio and improved cardiac function as measured by echocardiography was evident in animals treated with STAT3 inhibitor or siRNA. Compared with IL-6 neutralization, more pronounced down-regulation of collagen synthesis and regression of hypertrophy was observed with STAT3 inhibition, suggesting that STAT3 is the major downstream signaling molecule and a potential therapeutic target for cardiac hypertrophy.Cardiac fibrosis is considered to be a major player during hypertrophy, where excess synthesis and a disproportionate accumulation of extracellular matrix proteins in the myocardium leads to its stiffness and diastolic dysfunction, leading to heart failure (1-3). Fibrillar collagen 1 and collagen 3 are the most abundant extracellular matrix proteins in the myocardium that maintain myocardial structural integrity (4). Collagen biosynthesis process is mainly compartmentalized in cardiac fibroblasts with a continuous turnover of newly synthesized collagen and degradation of old existing collagen, which involves post-transcriptional as well as post translational events. A physiological balance exists between collagen synthesis and degradation that is necessary to maintain tissue integrity of the myocardium. Extracellular catalytic cleavage of collagen is mediated by matrix metalloproteinases (MMPs) 2 that are eventually regulated by their naturally occurring endogenous inhibitors, i.e. tissue inhibitors of metalloproteinases (TIMPs) (1, 5).The fine balance between MMPs and TIMPs plays a crucial role in regulation of cardiac collagen turnover (5, 6). Furthermore, lysyl oxidase (LOX) is also instrumental during collagen biogenesis that catalyzes lysine-derived cross-bridges between two or more lysine residues of nascent procollagen peptides during their maturation into collagen molecules (5, 7). Altered and deregulated expression of these factors has been demonstrated in failing myocardium (5).Involvem...

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

Cited by 184 publications

References 170 publications

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

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

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

Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) Attenuates Interleukin-6 (IL-6)-induced Collagen Synthesis and Resultant Hypertrophy in Rat Heart

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