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Cited by 34Cytokine Signaling Pathways and InteractionsRedox biology and oxidative stressNitric Oxide and Endothelin Effects

Acyloxy nitroso compounds inhibit LIF signaling in endothelial cells and cardiac myocytes: evidence that STAT3 signaling is redox-sensitive

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Zgheib, Carlos, Kurdi, Mazen, Zouein, Fouad A., Gunter, Barak W., Stanley, Brian A., Zgheib, Joe, Romero, Damian G., King, S. Bruce +2 more·2012·PLoS ONE
DOI 10.1371/journal.pone.0043313PMC PMC3419695
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Abstract

We previously showed that oxidative stress inhibits leukemia inhibitory factor (LIF) signaling by targeting JAK1, and the catalytic domains of JAK 1 and 2 have a cysteine-based redox switch. Thus, we postulated that the NO sibling and thiophylic compound, nitroxyl (HNO), would inhibit LIF-induced JAK-STAT3 activation. Pretreatment of human microvascular endothelial cells (HMEC-1) or neonatal rat cardiomyocytes with the HNO donors Angeli's salt or nitrosocyclohexyl acetate (NCA) inhibited LIF-induced STAT3 activation. NCA pretreatment also blocked the induction of downstream inflammatory genes (e.g. intercellular adhesion molecule 1, CCAAT/enhancer binding protein delta). The related 1-nitrosocyclohexyl pivalate (NCP; not a nitroxyl donor) was equally effective in inhibiting STAT3 activation, suggesting that these compounds act as thiolate targeting electrophiles. The JAK1 redox switch is likely not a target of acyloxy nitroso compounds, as NCA had no effect on JAK1 catalytic activity and only modestly affected JAK1-induced phosphorylation of the LIF receptor. However, pretreatment of recombinant human STAT3 with NCA or NCP reduced labeling of free sulfhydryl residues. We show that NCP in the presence of diamide enhanced STAT3 glutathionylation and dimerization in adult mouse cardiac myocytes and altered STAT3 under non-reducing conditions. Finally, we show that monomeric STAT3 levels are decreased in the Gαq model of heart failure in a redox-sensitive manner. Altogether, our evidence indicates that STAT3 has redox-sensitive cysteines that regulate its activation and are targeted by HNO donors and acyloxy nitroso compounds. These findings raise the possibility of new therapeutic strategies to target STAT3 signaling via a redox-dependent manner, particularly in the context of cardiac and non-cardiac diseases with prominent pro-inflammatory signaling.

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  • Thiol-targeting agents inhibit IL-6-induced STAT3 activation by S-glutathionylation in HepG2 cells, human endothelial cells, neonatal rat cardiomyocytes, and adult mouse cardiac myocytes.

    “thiol-targeting agents also inhibited IL-6–induced STAT3 activation by S-glutathionylation in HepG2 cells (Xie et al., 2009), human endothelial cells, neonatal rat cardiomyocytes, and adult mouse cardiac myocytes (Zgheib et al., 2012)”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Zgheib et al., 2012

    The Results and Figures 2–3 report that thiol-reactive compounds inhibited LIF-induced, not IL-6-induced, STAT3 activation in human endothelial cells and neonatal rat and adult-phenotype mouse cardiac myocytes. The Results section “NCP Enhances STAT3 Glutathionylation and Dimerization” reports glutathionylation in HL-1 cells only when NCP and diamide were combined; it does not establish S-glutathionylation as the cause of the inhibition across the cited cell types. The HepG2 finding is separately attributed to Xie et al. in the citing sentence. (LLM, conf=0.90)

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Authors
Zgheib, C., Kurdi, M., Zouein, F. A., Gunter, B. W., Stanley, B. A., Zgheib, J., Romero, D. G., King, S. B., Paolocci, N., & Booz, G. W.
Affiliations
  • University of Mississippi Medical Center (US)
  • Lebanese University (LB)
  • Johns Hopkins University (US)
  • Centre Hospitalier Régional et Universitaire de Nancy (FR)
  • Wake Forest University (US)
Corresponding author
Booz, George W.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-08-15
Volume
7
Issue
8
Pages
e43313
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0043313
PMC
PMC3419695
OpenAlex
W1981721279
Cited by
34
References
1
Citations by year
2025: 1 · 2022: 2 · 2021: 1 · 2020: 4 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 7 · 2015: 1 · 2014: 7 · 2013: 4 · 2012: 1
FWCI
2.22
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Université Libanaise
  • Centre National de la Recherche Scientifique
  • Ministerial Standing Committee on Scientific and Technological Cooperation of the Organization of Islamic Cooperation
  • National Heart, Lung, and Blood Institute (R01HL62198, R01HL088101, R01HL091923, R01HL062198)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
STAT3 activation, nitroxyl donors, JAK/STAT3 signaling, redox regulation, glutathionylation, endothelial cells, cardiomyocytes, heart failure, Gαq, inflammatory gene expression, ICAM-1, C/EBPδ, diamide
MeSH terms
Animals, Endothelium, Vascular, Glutathione, Humans, Inflammation, Male, Mice, Inbred C57BL, Microcirculation, Nitrogen, Oxidation-Reduction, Phosphorylation, Signal Transduction, Rats, Sprague-Dawley, Oxidative Stress, Muscle Cells, Myocytes, Cardiac, STAT3 Transcription Factor, Mice, Rats, Leukemia Inhibitory Factor

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