Activation of Signal Transducer and Activator of Transcription 3 Protects Cardiomyocytes from Hypoxia/Reoxygenation-Induced Oxidative Stress Through the Upregulation of Manganese Superoxide Dismutase

Negoro, Shinji; Kunisada, Keita; Fujio, Yasushi; Funamoto, Masanobu; Darville, Martine I.; Eizirik, Décio L.; Osugi, Tomoaki; Izumi, Mitsuru; Oshima, Yoshifumi; Nakaoka, Yoshikazu; Hirota, Hisao; Kishimoto, Tadamitsu; Yamauchi–Takihara, Keiko

doi:10.1161/hc3401.095947

Cited by 228 publications

(177 citation statements)

References 23 publications

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“…We postulate that during cell stress STAT3 is an anti-apoptotic factor that works both as a signaling molecule involved in regulation of gene expression (1,3,4) and as a direct immediate modulator of the mitochondrial electron transport chain (Fig. 3).…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of tissuespecific conditional STAT3 knock-out mice has provided strong evidence that transcriptional activity of STAT3 plays a central role in the control of cell growth and host responses to inflammation and cellular stress (1). STAT3 positively regulates expression of anti-apoptotic (Bcl-2 and Bcl-xL) (1) and antioxidative proteins (MnSOD and metallothionein-1 and -2) (3,4).…”

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confidence: 99%

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Mitochondrial-targeted Signal Transducer and Activator of Transcription 3 (STAT3) Protects against Ischemia-induced Changes in the Electron Transport Chain and the Generation of Reactive Oxygen Species

Szczepanek

Chen

Derecka

et al. 2011

Journal of Biological Chemistry

198

229

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Expression of the STAT3 transcription factor in the heart is cardioprotective and decreases the levels of reactive oxygen species. Recent studies indicate that a pool of STAT3 resides in the mitochondria where it is necessary for the maximal activity of complexes I and II of the electron transport chain. However, it has not been explored whether mitochondrial STAT3 modulates cardiac function under conditions of stress. Transgenic mice with cardiomyocyte-specific overexpression of mitochondria-targeted STAT3 with a mutation in the DNA-binding domain (MLS-STAT3E) were generated. We evaluated the role of mitochondrial STAT3 in the preservation of mitochondrial function during ischemia. Under conditions of ischemia heart mitochondria expressing MLS-STAT3E exhibited modest decreases in basal activities of complexes I and II of the electron transport chain. In contrast to WT hearts, complex I-dependent respiratory rates were protected against ischemic damage in MLS-STAT3E hearts. MLS-STAT3E prevented the release of cytochrome c into the cytosol during ischemia. In contrast to WT mitochondria, ischemia did not augment reactive oxygen species production in MLS-STAT3E mitochondria likely due to an MLS-STAT3E-mediated partial blockade of electron transport through complex I. Given the caveat of STAT3 overexpression, these results suggest a novel protective mechanism mediated by mitochondrial STAT3 that is independent of its canonical activity as a nuclear transcription factor. STAT3 was originally identified as an IL-6-induced transcriptional activator of acute phase genes (1). However, other members of the IL-6 family, which utilize gp-130 receptor, as well as leptin, IL-12, IFN␣/␤, IL-10, GM-CSF, several growth factors, oncogenes, and stress such as hypoxia, also activate STAT3 (1). STAT3 is vital to embryonic development and STAT3-null mice are embryonic lethal (2). Analysis of tissuespecific conditional STAT3 knock-out mice has provided strong evidence that transcriptional activity of STAT3 plays a central role in the control of cell growth and host responses to inflammation and cellular stress (1). STAT3 positively regulates expression of anti-apoptotic (Bcl-2 and Bcl-xL) (1) and antioxidative proteins (MnSOD and metallothionein-1 and -2) (3, 4).Expression of STAT3 in the heart is associated with cardiac survival (5). When STAT3 is selectively deleted in cardiomyocytes, mice develop enhanced cardiac inflammation with fibrosis, dilated cardiomyopathy, and die prematurely due to congestive heart failure (5). Female mice, where STAT3 is not expressed in cardiomyocytes, develop post-partum cardiomyopathy, which is also seen in humans with reduced STAT3 expression in the myocardium (6). Ventricles from STAT3-null hearts show elevated levels of reactive oxygen species (ROS) 2 (6). Ischemic and pharmacologic preconditioning protected the viability of wild type but not STAT3 Ϫ/Ϫ cardiomyocytes (5). When STAT3 is overexpressed in cardiomyocytes, mice are less sensitive to the cardiotoxic effects of doxorubicin, which exerts i...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Mitochondrial-targeted Signal Transducer and Activator of Transcription 3 (STAT3) Protects against Ischemia-induced Changes in the Electron Transport Chain and the Generation of Reactive Oxygen Species

Szczepanek

Chen

Derecka

et al. 2011

Journal of Biological Chemistry

198

229

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“…STAT3 overexpression results in decreased infarct size induced by ischemia/reperfusion injury and gives protection to cardiac myocytes during hypoxia/reoxygenation induced cell loss (37,38). Heart failure patients with end stage-dilated cardiomyopathy shows increased tyrosine phosphorylation of STAT3, but it is also established that STAT3 activation is instrumental in inhibition of apoptosis and necessary to promote compensatory hypertrophy and thus helps in prevention of heart failure (39).…”

Section: Discussionmentioning

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

126

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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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“…The Janus activated kinase (JAK) and Signal Transducer and Activator of Transcription 3 (STAT3) signalling pathway is responsive to a large number of cytokines, growth factors and hormones [6,7,18], and is known to play a vital role in cardioprotection related to ischemia-reperfusion (I/R) injury [2,13,16,24,26,28,29,39,46]. This pathway is activated by a diversity of receptors, including receptor tyrosine kinases [38,45,51] and Gprotein-coupled receptors [11,33].…”

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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Activation of Signal Transducer and Activator of Transcription 3 Protects Cardiomyocytes from Hypoxia/Reoxygenation-Induced Oxidative Stress Through the Upregulation of Manganese Superoxide Dismutase

Cited by 228 publications

References 23 publications

Mitochondrial-targeted Signal Transducer and Activator of Transcription 3 (STAT3) Protects against Ischemia-induced Changes in the Electron Transport Chain and the Generation of Reactive Oxygen Species

Mitochondrial-targeted Signal Transducer and Activator of Transcription 3 (STAT3) Protects against Ischemia-induced Changes in the Electron Transport Chain and the Generation of Reactive Oxygen Species

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

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

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