RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K
            <sup>+</sup>
            channels

Rottlaender, Dennis; Boengler, Kerstin; Wolny, Martin; Schwaiger, Astrid; Motloch, Lukas J.; Ovize, Michel; Schulz, Rainer; Heusch, Gerd; Hoppe, Uta C.

doi:10.1073/pnas.1107479109

Cited by 26 publications

(18 citation statements)

References 42 publications

(69 reference statements)

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“…Further studies are required to elucidate whether the phosphorylation states of Cx43, at sites other than S368, alter or are involved in the pathogenesis of DCM. As a regulator of the mitochondrial physiology, cardiac mtCx43 may target mitochondrial adenosine triphosphate-sensitive K + channels (30). Furthermore, reactive oxygen species formation is reported to be impaired in the cardiomyocytes of Cx43 -/-mice (4) and cytochrome c and Ca…”

Section: Discussionmentioning

confidence: 99%

Suppression of PKCε-mediated mitochondrial connexin 43 phosphorylation at serine 368 is involved in myocardial mitochondrial dysfunction in a rat model of dilated cardiomyopathy

Huang

Wei

Zhang

et al. 2015

Molecular Medicine Reports

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Abstract. Mitochondrial connexin 43 (Cx43) is important in cardioprotection by ischemic preconditioning; however, whether mitochondrial Cx43 is involved in mitochondrial dysfunction in the pathogenesis of dilated cardiomyopathy (DCM) remains to be elucidated. The present study was performed to investigate the changes in expression and the phosphorylation state of mitochondrial Cx43 in a rat model of DCM, and to determine whether the altered phosphorylation state of mitochondrial Cx43 was involved in mitochondrial dysfunction. A rat model of DCM was generated by daily oral administration of furazolidone (FZD) for 30 weeks. Reverse transcription polymerase chain reaction and western blot analysis revealed a decrease in the overall expression of Cx43, accompanied by reduced levels of serine 368-phosphorylated-Cx43 immunoreactivity in the myocardium and myocardial mitochondria. In addition, the mitochondrial membrane potential and the activities of cytochrome c oxidase, succinate dehydrogenase and protein kinase C (PKC) ε were all significantly reduced compared with those of the control group. Phorbol-12-myristate-13-acetate (PMA), a specific PKC activator, partially reversed the FZD-induced mitochondrial Cx43 dephosphorylation at serine 368 and mitochondrial dysfunction in the cardiomyocytes. However, pretreatment with 18β-glycerrhetinic acid, a connexin channel inhibitor, eliminated the mitochondrial protective effect of PMA in the cardiomyocytes sparsely plated without cell to cell contact. These results suggested that dephosphorylation of mitochondrial Cx43 at serine 368, due to the suppression of PKCε activity, may be a novel mechanism for mitochondrial dysfunction in the pathogenesis of DCM.

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Section: Discussionmentioning

confidence: 99%

Suppression of PKCε-mediated mitochondrial connexin 43 phosphorylation at serine 368 is involved in myocardial mitochondrial dysfunction in a rat model of dilated cardiomyopathy

Huang

Wei

Zhang

et al. 2015

Molecular Medicine Reports

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“…Suppression of GSK3β mediates cardioprotection during I/R by regulating the mPTP opening through direct phosphorylation, thereby inducing mitochondrial depolarization release of cytocrorm c, and eventual cell death [46]. More recently, it was shown that inhibition of GSK3β transfers cytoprotective signaling through mitochondrial Cx43 onto mitoK ATP channels [52], the opening of which has been linked with rapamycin-induced cardioprotection as we reported previously [7]. Recent study suggested that the activity of GSK3β is differentially regulated by ischemia and I/R.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin protects against myocardial ischemia–reperfusion injury through JAK2–STAT3 signaling pathway

Das

Salloum

Durrant

et al. 2012

Journal of Molecular and Cellular Cardiology

115

103

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Rapamycin (Sirolimus®) is used to prevent rejection of transplanted organs and coronary restenosis. We reported that rapamycin induced cardioprotection against ischemia-reperfusion (I/R) injury through opening of mitochondrial KATP channels. However, signaling mechanisms in rapamycin-induced cardioprotection are currently unknown. Considering that STAT3 is protective in the heart, we investigated the potential role of this transcription factor in rapamycin-induced protection against (I/R) injury. Adult male ICR mice were treated with rapamycin (0.25 mg/kg, i.p.) or vehicle (DMSO) with/without inhibitor of JAK2 (AG-490) or STAT3 (stattic). One hour later, the hearts were subjected to I/R either in Langendorf mode or in situ ligation of left coronary artery. Additionally, primary murine cardiomyocytes were subjected to simulated ischemia/reoxygenation (SI-RO) injury in vitro. For in situ targeted knockdown of STAT3, lentiviral vector containing short hairpin RNA was injected into left ventricle 3 weeks prior to initiating I/R injury. Infarct size, cardiac function, cardiomyocyte necrosis and apoptosis were assessed. Rapamycin reduced infarct size, improved cardiac function following I/R, limited cardiomyocytes necrosis as well as apoptosis following SI-RO which were blocked by AG-490 and stattic. In situ knock-down of STAT3 attenuated rapamycin-induced protection against I/R injury. Rapamycin triggered unique cardioprotecive signaling including phosphorylation of ERK, STAT3, eNOS and glycogen synthase kinase-3β in concert with increased prosurvival Bcl-2 to Bax ratio. Our data suggest that JAK2-STAT3 signaling plays an essential role in rapamycin-induced cardioprotection. We propose that rapamycin is a novel and clinically relevant pharmacological strategy to target STAT3 activation for treatment of myocardial infarction.

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“…Phosphorylation of GSK3β has been demonstrated to be a critical integration point of preconditioning pathways involving regulation of mitochondrial metabolism and permeability pore transition . p‐GSK3β has been shown to be colocalized in mitochondria with p‐Connexin43, which enables increased open probability of mitochondrial K ATP channels and cardioprotection . Connexin43 is an integral membrane protein whose role in gap junction formation is essential in maintaining electrical and mechanical coupling between cardiomyocytes; however, phosphorylation of Connexin43 enables translocation to mitochondria to permit cardioprotection .…”

Section: Discussionmentioning

confidence: 99%

Effect of Remote Ischemic Preconditioning on Phosphorylated Protein Signaling in Children Undergoing Tetralogy of Fallot Repair: A Randomized Controlled Trial

Pepe

Liaw

Hepponstall

et al. 2013

JAHA

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BackgroundOur previous randomized controlled trial demonstrated cardiorespiratory protection by remote ischemic preconditioning (RIPC) in children before cardiac surgery. However, the impact of RIPC on myocardial prosurvival intracellular signaling remains unknown in cyanosis. RIPC may augment phosphorylated protein signaling in myocardium and circulating leukocytes during tetralogy of Fallot (ToF) repair.Methods and ResultsChildren (n=40) undergoing ToF repair were double‐blind randomized to RIPC (n=11 boys, 9 girls) or control (sham RIPC: n=9 boys, 11 girls). Blood samples were taken before, immediately after, and 24 hours after cardiopulmonary bypass. Resected right ventricular outflow tract muscle and leukocytes were processed for protein expression and mitochondrial respiration. There was no difference in age (7.1±3.4 versus 7.1±3.4 months), weight (7.7±1.8 versus 7.5±1.9 kg), or bypass or aortic cross‐clamp times between the groups (control versus RIPC, mean±SD). No differences were seen between the groups for an increase in the ratio of phosphorylated to total protein for protein kinase B, p38 mitogen activated protein kinase, signal transducer and activator of transcription 3, glycogen synthase kinase 3β, heat shock protein 27, Connexin43, or markers associated with promotion of necrosis (serum cardiac troponin I), apoptosis (Bax, Bcl‐2), and autophagy (Parkin, Beclin‐1, LC3B). A high proportion of total proteins were in phosphorylated form in control and RIPC myocardium. In leukocytes, mitochondrial respiration and assessed protein levels did not differ between groups.ConclusionsIn patients with cyanotic heart disease, a high proportion of proteins are in phosphorylated form. RIPC does not further enhance phosphorylated protein signaling in myocardium or circulating leukocytes in children undergoing ToF repair.Clinical Trial RegistrationURL: (http://www.anzctr.org.au/trial_view.aspx?id=335613. Unique identifier: Australian New Zealand Clinical Trials Registry number ACTRN12610000496011.

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RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels

Cited by 26 publications

References 42 publications

Suppression of PKCε-mediated mitochondrial connexin 43 phosphorylation at serine 368 is involved in myocardial mitochondrial dysfunction in a rat model of dilated cardiomyopathy

Suppression of PKCε-mediated mitochondrial connexin 43 phosphorylation at serine 368 is involved in myocardial mitochondrial dysfunction in a rat model of dilated cardiomyopathy

Rapamycin protects against myocardial ischemia–reperfusion injury through JAK2–STAT3 signaling pathway

Effect of Remote Ischemic Preconditioning on Phosphorylated Protein Signaling in Children Undergoing Tetralogy of Fallot Repair: A Randomized Controlled Trial

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RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K + channels

Cited by 26 publications

References 42 publications

Suppression of PKCε-mediated mitochondrial connexin 43 phosphorylation at serine 368 is involved in myocardial mitochondrial dysfunction in a rat model of dilated cardiomyopathy

Suppression of PKCε-mediated mitochondrial connexin 43 phosphorylation at serine 368 is involved in myocardial mitochondrial dysfunction in a rat model of dilated cardiomyopathy

Rapamycin protects against myocardial ischemia–reperfusion injury through JAK2–STAT3 signaling pathway

Effect of Remote Ischemic Preconditioning on Phosphorylated Protein Signaling in Children Undergoing Tetralogy of Fallot Repair: A Randomized Controlled Trial

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RETRACTED: Glycogen synthase kinase 3β transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K ⁺ channels