Role of JAK-STAT pathway in reducing cardiomyocytes hypoxia/reoxygenation injury induced by S1P postconditioning

Wang, Yuqing; Wang, Dongfei; Zhang, Lizhi; Ye, Fangyu; Li, Mengmeng; Wen, Ke

doi:10.1016/j.ejphar.2016.05.024

Cited by 21 publications

(12 citation statements)

References 50 publications

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“…IL-6 significantly increased APD at 90% repolarization (APD 90 ) from 310±12.4 ms ( Black trace) , to 371±13.9 ms ( Red trace; 19%, n = 11, *P<0.05 , Fig 8E and 8F ), but had a more pronounced effect in the presence of IL-6R ( Grey trace ) as APD 90 increased to 408±27.8 ms (or by 32%, n = 14, *P<0.05). Inhibition of JAK with JAK inhibitor-I (5 μM, Cyan trace ) [38], or AG490 (5 μM, Orange trace ) [40], completely prevented APD prolongation ( Fig 8E and 8F ). Compared to control APD 90 (310±12.4 ms), values were 312.5±24.7 ms (P>0.05, n = 7, Fig 8E and 8F ) and 325.5±9.43 ms (n = 6, P>0.05, Fig 8E ) with JAK inhibitor and AG490 respectively.…”

Section: Resultsmentioning

confidence: 99%

Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation

et al. 2018

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Increased proinflammatory interleukin-6 (IL-6) levels are associated with acquired long QT-syndrome (LQTS) in patients with systemic inflammation, leading to higher risks for life-threatening polymorphic ventricular tachycardia such as Torsades de Pointes. However, the functional and molecular mechanisms of this association are not known. In most cases of acquired LQTS, the target ion channel is the human ether-á-go-go-related gene (hERG) encoding the rapid component of the delayed rectifier K current, IKr, which plays a critical role in cardiac repolarization. Here, we tested the hypothesis that IL-6 may cause QT prolongation by suppressing IKr. Electrophysiological and biochemical assays were used to assess the impact of IL-6 on the functional expression of IKr in HEK293 cells and adult guinea-pig ventricular myocytes (AGPVM). In HEK293 cells, IL-6 alone or in combination with the soluble IL-6 receptor (IL-6R), produced a significant depression of IKr peak and tail current densities. Block of IL-6R or Janus kinase (JAK) reversed the inhibitory effects of IL-6 on IKr. In AGPVM, IL-6 prolonged action potential duration (APD) which was further prolonged in the presence of IL-6R. Similar to heterologous cells, IL-6 reduced endogenous guinea pig ERG channel mRNA and protein expression. The data are first to demonstrate that IL-6 inhibition of IKr and the resulting prolongation of APD is mediated via IL-6R and JAK pathway activation and forms the basis for the observed clinical QT interval prolongation. These novel findings may guide the development of targeted anti-arrhythmic therapeutic interventions in patients with LQTS and inflammatory disorders.

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Section: Resultsmentioning

confidence: 99%

Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation

et al. 2018

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“…There is evidence implicating the JAK-STAT pathway in both neuroprotection from cerebral ischemia, and in myocardial preservation after ischemia. Specifically, the JAK-STAT pathway was involved in Post-C preventing damage from global cerebral ischemia and myocardial ischemia [47–50], suggesting a possible role in retinal ischemic Post-C as well. But there are novel genes in the pathway identified in this study which have not been previously studied in ischemic injury or neuroprotection, including Il23a and Csf2, which may be drug targets to examine in future studies.…”

Section: Discussionmentioning

confidence: 99%

Gene expression in retinal ischemic post-conditioning

Kadzielawa

Mathew

Stelman

et al. 2018

Graefes Arch Clin Exp Ophthalmol

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“…In a study on H9c2 cells, another team reported that pharmacological post-conditioning with S1P involves JAK-STAT3 activation. The use of AG490 or Stattic abolished the protective effect of S1P, again pointing out the necessity of this pathway in achieving the protective effect (81).…”

Section: Roles Of Stat3 In Cardiomyocyte Pathologiesmentioning

confidence: 98%

An Update on the Multifaceted Roles of STAT3 in the Heart

Harhous

Booz

Ovize

et al. 2019

Front. Cardiovasc. Med.

101

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Signal transducer and activator of transcription 3 (STAT3) is a signaling molecule and transcription factor that plays important protective roles in the heart. The protection mediated by STAT3 is attributed to its genomic actions as a transcription factor and other non-genomic roles targeting mitochondrial function and autophagy. As a transcription factor, STAT3 upregulates genes that are anti-oxidative, anti-apoptotic, and pro-angiogenic, but suppresses anti-inflammatory and anti-fibrotic genes. Its suppressive effects on gene expression are achieved through competing with other transcription factors or cofactors. STAT3 is also linked to the modification of mRNA expression profiles in cardiac cells by inhibiting or inducing miRNA. In addition to these genomic roles, STAT3 is suggested to function protectively in mitochondria, where it regulates ROS production, in part by regulating the activities of the electron transport chain complexes, although our recent evidence calls this role into question. Nonetheless, STAT3 is a key player known to be activated in the cardioprotective ischemic conditioning protocols. Through these varied roles, STAT3 participates in various mechanisms that contribute to cardioprotection against different heart pathologies, including myocardial infarction, hypertrophy, diabetic cardiomyopathy, and peripartum cardiomyopathy. Understanding how STAT3 is involved in the protective mechanisms against these different cardiac pathologies could lead to novel therapeutic strategies to treat them.

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Role of JAK-STAT pathway in reducing cardiomyocytes hypoxia/reoxygenation injury induced by S1P postconditioning

Cited by 21 publications

References 50 publications

Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation

Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation

Gene expression in retinal ischemic post-conditioning

An Update on the Multifaceted Roles of STAT3 in the Heart

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