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Cited by 67Cytokine Signaling Pathways and InteractionsReceptor Mechanisms and SignalingCardiac electrophysiology and arrhythmias

Critical roles of STAT3 in β-adrenergic functions in the heart

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Zhang, Wenjun, Qu, Xiuxia, Chen, Biyi, Snyder, Marylynn, Wang, Meijing, Li, Baiyan, Tang, Yue, Chen, Hanying +12 more·2016·Circulation
DOI 10.1161/circulationaha.115.017472PMC PMC4698100
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Abstract

Background—: β-Adrenergic receptors (βARs) play paradoxical roles in the heart. On one hand, βARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of βARs exert deleterious effects that result in heart failure. The signal transducer and activator of transcription 3 (STAT3) plays a dynamic role in integrating multiple cytokine signaling pathways in a number of tissues. Altered activation of STAT3 has been observed in failing hearts in both human patients and animal models. Our objective is to determine the potential regulatory roles of STAT3 in cardiac βAR-mediated signaling and function. Methods and Results—: We observed that STAT3 can be directly activated in cardiomyocytes by β-adrenergic agonists. To follow up this finding, we analyzed βAR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute βAR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic β-adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that Gα s and Src kinases are required for βAR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of βAR pathway, including β 1 AR, protein kinase A, and T-type Ca 2+ channels. Conclusions—: Our data demonstrate for the first time that STAT3 has a fundamental role in βAR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for βAR-mediated cardiac stress adaption, pathological remodeling, and heart failure.

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  • IL-6 treatment reduces endothelial disruption and neutrophil sequestration in lung and alveolar spaces, resulting in improved oxygenation after I/R.

    “IL-6 treatment also reduced endothelial disruption and neutrophil sequestration in lung and alveolar spaces, resulting in improved oxygenation after I/R (Zhang et al., 2016).”

    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 Zhang et al., 2016

    The Results section on β-adrenergic STAT3 activation mentions an IL-6-family cytokine only as a laboratory positive control. The Results on chronic β-adrenergic stimulation concern cardiac injury, not lung injury. Searches for neutrophil sequestration, endothelial disruption, oxygenation, and lung ischemia/reperfusion found no passage addressing the attributed claim. (LLM, conf=0.76)

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Cited by

Sorted by citations

Authors
Zhang, W., Qu, X., Chen, B., Snyder, M., Wang, M., Li, B., Tang, Y., Chen, H., Zhu, W., Zhan, L., Yin, N., Li, D., Xie, L., Liu, Y., Zhang, J. J., Fu, X.-Y., Rubart, M., Song, L.-S., Huang, X.-Y., & Shou, W.
Affiliations
  • University of Iowa (US)
  • From State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (W. Zhang, X.Q., Y.T., W.S.); Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indianapolis, IN (W. Zhang, B.L., H.C., W. Zhu, L.Z., N.Y., D.L., L.X., Y.L., M.R., W.S.); Department of Internal Medicine, Carver College of Medicine, University of Iowa,...
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2016-01-05
Volume
133
Issue
1
Pages
48-61
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.115.017472
PMC
PMC4698100
OpenAlex
W2183417521
Cited by
67
References
0
Citations by year
2026: 5 · 2025: 3 · 2024: 7 · 2023: 10 · 2022: 3 · 2021: 8 · 2020: 11 · 2019: 9 · 2018: 6 · 2017: 2 · 2016: 2 · 2015: 1
FWCI
1.60
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • Purdue University Indianapolis (Indiana University) (submittedVersion)
Funders
  • National Institute on Alcohol Abuse and Alcoholism (U01AA023503, R01AA023503)
  • National Heart, Lung, and Blood Institute (R01HL090905, R01HL081092, HL 91525, HL090905, R01HL130346, R01HL091525, HL81092)
  • National Cancer Institute (CA125568-05, R01CA125568)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
STAT3, beta-adrenergic receptors, heart failure, cardiomyocytes, cardiac contractility, cardiomyocyte hypertrophy, myocardial fibrosis, Gs protein, Src kinase, protein kinase A, T-type calcium channels, beta1-adrenergic receptor, transcriptional regulation, cardiac remodeling
MeSH terms
Adrenergic beta-Agonists, Animals, Cell Line, Heart, Male, Mice, Inbred C57BL, Organ Culture Techniques, Receptors, Adrenergic, beta, Mice, Knockout, Myocytes, Cardiac, STAT3 Transcription Factor, Mice

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