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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.

ABSTRACT: 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.

SUBMITTER: Szczepanek K

PROVIDER: S-EPMC3191002 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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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 Karol K Chen Qun Q Derecka Marta M Salloum Fadi N FN Zhang Qifang Q Szelag Magdalena M Cichy Joanna J Kukreja Rakesh C RC Dulak Jozef J Lesnefsky Edward J EJ Larner Andrew C AC

The Journal of biological chemistry 20110629 34

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-ta ...[more]

PMID: 21715323

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Project description:Study questionAre STAT3 signaling molecules differentially expressed in endometriosis?Summary answerLevels of phospho-STAT3 and HIF1A, its downstream signaling molecule, are significantly higher in eutopic endometrium from women with endometriosis when compared with women without the disease.What is known alreadyEndometriosis is an estrogen-dependent inflammatory condition. Interleukin 6 (IL-6) is an inflammatory survival cytokine known to induce prolonged activation of STAT3 via association with the IL-6 receptor.Study design, size, durationCross-sectional measurements of STAT3 and HIF1A protein levels in eutopic endometrium from women with endometriosis versus those without.Participants/materials, setting, methodsLevels of phospho-STAT3 (pSTAT3) and HIF1A were examined in the endometrium of patients with and without endometriosis as well as in a non-human primate animal model using western blot and immunohistochemical analysis.Main results and the role of chanceLevels of pSTAT3 were significantly higher in the eutopic endometrium from women with endometriosis when compared with women without the disease in both the proliferative and secretory phases. HIF1A is known to be stabilized by STAT3 and IL-6. Our immunohistochemistry results show abundant HIF1A expression within the eutopic endometrial epithelial cells of women with endometriosis. Furthermore, pSTAT3 and HIF1A proteins are co-localized in endometriosis. This aberrant activation of pSTAT3 and HIF1A is confirmed by sequential analysis of eutopic endometrium using a baboon animal model of induced endometriosis. Lastly, we confirmed this IL-6 induction of both STAT3 phosphorylation and HIF1A mRNA expression in Ishikawa human endometrial adenocarcinoma cell line.Limitations, reasons for cautionIshikawa cancer cell line was used to study a benign disease. The peritoneal fluid contains various inflammatory cytokines in addition to IL-6 and so it is possible that other cytokines may affect the activity and expression of STAT3 signaling molecules.Wider implications of the findingsOur results imply that aberrant activation of STAT3 signaling plays an important role in the pathogenesis of endometriosis. Our findings could progress in our understanding of the etiology and pathophysiology of endometriosis and potential therapeutic interventions by targeted pharmacological.Study funding/competing interestsThis work was supported by NIH R01 HD067721 (to S.L.Y and B.A.L) and NIH R01 HD057873 and American Cancer Society Research Grant RSG-12-084-01-TBG (to J.-W.J.). There are no conflicts of interest.

Project description:BackgroundThere is growing evidence about the effect of bilateral superior cervical sympathectomy on myocardial ischemia-reperfusion (I/R) injury. Studies have increasingly found that the signal transducer and activator of transcription 3 (STAT3) plays a protective role in myocardial I/R injury. However, the precise mechanism is unknown. The present study explored the bilateral superior cervical sympathectomy's effect and potential mechanism in mice myocardial I/R injury.MethodsThe left heart I/R injury model was created by ligating the anterior descending branch of the coronary artery for 30 min followed by reperfusion. Bilateral superior cervical sympathectomy was performed before myocardial I/R injury. To evaluate the effect of bilateral superior cervical sympathectomy on the myocardium, we examined the myocardial infarct size and cardiac function. Then, myocardial apoptosis, inflammation, and oxidative stress were detected on the myocardium. Furthermore, the expression of STAT3 signal in myocardial tissue was measured by western blotting. To further examine the cardioprotective effect of STAT3 after bilateral superior cervical sympathectomy, the STAT3 inhibitor (static) was utilized to inhibit the phosphorylation of STAT3.ResultsThe results showed that the myocardial I/R injury decreased and the cardiac function recovered in the myocardial I/R injury after cervical sympathectomy. Meanwhile, cervical sympathectomy reduced the myocardial distribution of the sympathetic marker tyrosine hydroxylase (TH) and systemic sympathetic tone. And levels of oxidative stress, inflammatory markers, and apoptosis were reduced in myocardial tissue. We also found that the STAT3 signal was activated in myocardial tissue after cervical sympathectomy. STAT3 inhibitor can partially reverse the myocardial protective effect of cervical sympathectomy.ConclusionBilateral superior cervical sympathectomy significantly alleviated myocardial I/R injury in mice. And activation of the STAT3 signal may play an essential role in this.

Dataset Information

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.

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.

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