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Cited by 82Cytokine Signaling Pathways and InteractionsCardiac Ischemia and ReperfusionCardiac Fibrosis and Remodeling

Pivotal importance of STAT3 in protecting the heart from acute and chronic stress: new advancement and unresolved issues

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Zouein, Fouad A., Altara, Raffaele, Chen, Qun, Lesnefsky, Edward J., Kurdi, Mazen, Booz, George W.·2015·Frontiers in Cardiovascular Medicine
DOI 10.3389/fcvm.2015.00036PMC PMC4671345
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Abstract

The transcription factor, signal transducer and activator of transcription 3 (STAT3), has been implicated in protecting the heart from acute ischemic injury under both basal conditions and as a crucial component of pre- and post-conditioning protocols. A number of anti-oxidant and antiapoptotic genes are upregulated by STAT3 via canonical means involving phosphorylation on Y705 and S727, although other incompletely defined posttranslational modifications are involved. In addition, STAT3 is now known to be present in cardiac mitochondria and to exert actions that regulate the electron transport chain, reactive oxygen species production, and mitochondrial permeability transition pore opening. These non-canonical actions of STAT3 are enhanced by S727 phosphorylation. The molecular basis for the mitochondrial actions of STAT3 is poorly understood, but STAT3 is known to interact with a critical subunit of complex I and to regulate complex I function. Dysfunctional complex I has been implicated in ischemic injury, heart failure, and the aging process. Evidence also indicates that STAT3 is protective to the heart under chronic stress conditions, including hypertension, pregnancy, and advanced age. Paradoxically, the accumulation of unphosphorylated STAT3 (U-STAT3) in the nucleus has been suggested to drive pathological cardiac hypertrophy and inflammation via non-canonical gene expression, perhaps involving a distinct acetylation profile. U-STAT3 may also regulate chromatin stability. Our understanding of how the non-canonical genomic and mitochondrial actions of STAT3 in the heart are regulated and coordinated with the canonical actions of STAT3 is rudimentary. Here, we present an overview of what is currently known about the pleotropic actions of STAT3 in the heart in order to highlight controversies and unresolved issues.

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  • STAT3 undergoes post-translational modifications including methylation, acetylation, ubiquitination, ISGylation, and SUMOylation.

    “In addition to tyrosine phosphorylation, STAT3 also undergoes a variety of other post-translational modifications, including methylation, acetylation, ubiquitination, IFN-stimulated gene (ISG)-ylation, and small ubiquitin-related modifiers (SUMOs)-conjugation (SUMOylation) (Kojima et al., 2013; You et al., 2015; Zouein et al., 2015; Avalle and Poli, 2018; Hu et al., 2018) with various effects on”

    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 Zouein et al., 2015

    The Introduction’s “Posttranslational Modifications of STAT3” section (page unavailable) identifies methylation, acetylation, and mono-ubiquitination of STAT3. It does not identify ISGylation or SUMOylation, so this source supports only part of the attributed list. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Zouein, F. A., Altara, R., Chen, Q., Lesnefsky, E. J., Kurdi, M., & Booz, G. W.
Affiliations
  • American University of Beirut (LB)
  • University of Mississippi Medical Center (US)
  • Virginia Commonwealth University (US)
  • Lebanese University (LB)
Corresponding author
Booz, George W.
ORCID
Venue
Frontiers in Cardiovascular Medicine
Publisher
Frontiers Media SA
Published
2015-11-30
Volume
2
Pages
36-36
ISSN
2297-055X (ISSN-L)
DOI
10.3389/fcvm.2015.00036
PMC
PMC4671345
OpenAlex
W2214775869
Cited by
82
References
8
Citations by year
2026: 3 · 2025: 3 · 2024: 5 · 2023: 11 · 2022: 8 · 2021: 11 · 2020: 8 · 2019: 12 · 2018: 10 · 2017: 5 · 2016: 6
FWCI
0.75
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Cardiovascular Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American University of Beirut (100410)
  • U.S. Department of Veterans Affairs (1IO1BX001355-0A1)
  • Université Libanaise
  • American Heart Association
  • University of Mississippi
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
STAT3, myocardial ischemia, cardioprotection, preconditioning, postconditioning, mitochondrial STAT3, complex I, electron transport chain, reactive oxygen species, mitochondrial permeability transition pore, cardiac aging, hypertension, pregnancy, cardiac hypertrophy, cardiac inflammation, STAT3 acetylation, chromatin stability

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