Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age
Open accessAbstract
Cytokines and inflammation have been implicated in the pathogenesis of heart failure. For example, IL-6 family cytokines and the gp130 receptor play important roles in cardiac myocyte survival and hypertrophy. Signal transducer and activator of transcription 3 (STAT3) is a major signaling protein that is activated through gp130. We have created mice with a cardiomyocyte-restricted deletion of STAT3. As measured by serial echocardiograms, mice with cardiac specific deletion of STAT3 are significantly more susceptible to cardiac injury after doxorubicin treatment than age-matched controls. Intriguingly, STAT3 appears to have a critical role in protection of inflammation-induced heart damage. STAT3-deficient mice treated with lipopolysaccharide demonstrated significantly more apoptosis than their WT counterparts. At the cellular level, cardiomyocytes with STAT3 deleted secrete significantly more tumor necrosis factor α in response to lipopolysaccharide than those with WT STAT3. Furthermore, histologic examination of the cardiomyocyte-restricted STAT3-deficient mice reveals a dramatic increase in cardiac fibrosis in aged mice. Although no overt signs of heart failure are present in young STAT3-deficient mice, they spontaneously develop heart dysfunction with advancing age. These results indicate the crucial functions of STAT3 in cardiomyocyte resistance to inflammation and other acute injury and in pathogenesis of age-related heart failure.
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Cardiomyocyte-specific STAT3 knockout increases presbycardia and myocardial infarction susceptibility.
“Increased presbycardia and MI susceptibility”
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 Jacoby et al., 2003
The Results (page not provided) show greater age-related cardiac fibrosis and declining systolic function in mice with cardiomyocyte-specific STAT3 knockout, supporting the presbycardia portion. The paper reports greater susceptibility to doxorubicin-induced injury, not myocardial infarction. Its introductory mention of STAT3 activation during acute myocardial infarction does not establish increased infarction susceptibility after knockout. (LLM, conf=0.89)
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Research works printed but not linked: 2
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Cited by
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Self-citationMolecular Mechanisms in Heart Failure
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Aleshin, A., Ananthakrishnan, R., Li, Q., Rosario, R., Lu, Y., Qu, W., Song, F., Bakr, S., Szabolcs, M., D'Agati, V., et al. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01210.2007 · Cited by 143 · see citing works
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Many good reasons to have STAT3 in the heart
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Wohlgemuth, S. E., Calvani, R., & Marzetti, E. (2014) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2014.03.007 · Cited by 97 · see citing works
Yang, Z., Li, T., Xian, J., Chen, J., Huang, Y., Zhang, Q., Lin, X., Lu, H., & Lin, Y. (2022) · The FASEB Journal · doi:10.1096/fj.202200243r · Cited by 79 · see citing works
Hutchins, A. P., Diez, D., & Miranda-Saavedra, D. (2013) · JAK-STAT · doi:10.4161/jkst.25097 · Cited by 31 · see citing works
- Authors
- Jacoby, J. J., Kalinowski, A., Liu, M.-G., Zhang, S. S.-M., Gao, Q., Chai, G.-X., Ji, L., Iwamoto, Y., Li, E., Schneider, M., Russell, K. S., & Fu, X.-Y.
- Affiliations
- Harvard University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-10-17
- Volume
- 100
- Issue
- 22
- Pages
- 12929-12934
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC240721
- OpenAlex
- W1991447679
- Cited by
- 357
- References
- 0
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 10 · 2023: 8 · 2022: 11 · 2021: 12 · 2020: 17 · 2019: 14 · 2018: 16 · 2017: 27 · 2016: 25 · 2015: 16 · 2014: 18 · 2013: 19 · 2012: 23
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ar044906-05)
- National Institute of Allergy and Infectious Diseases (AI-34522, R01AI034522)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR44906)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
- Keywords
- STAT3, cardiomyocyte-specific knockout, inflammation, myocardial fibrosis, heart failure, aging, doxorubicin cardiotoxicity, lipopolysaccharide, apoptosis, TNF-α, gp130, IL-6 family cytokines, cardiomyocyte injury, cardiac dysfunction
- MeSH terms
- Aging, Alleles, Animals, DNA-Binding Proteins, Doxorubicin, Echocardiography, Fibrosis, Heart Failure, Inflammation, Myocardium, Tumor Necrosis Factor-alpha, Trans-Activators, Ventricular Function, Left, Mice, Knockout, Muscle Cells, STAT3 Transcription Factor, Mice
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