Genetic depletion of cardiac myocyte STAT-3 abolishes classical preconditioning
Abstract
Objective To evaluate the functional requirement of signal transducer and activator of transcription-3 (STAT-3) in cardiac myocyte tolerance to ischemia (I) and in classical preconditioning. Methods Cardiac myocyte STAT-3 was depleted in mice using Cre-lox p technology. Isolated cardiomyocytes from wild-type (WT) and STAT-3-deficient mice were evaluated for viability following simulated ischemia (SI; 26 h). Cardiomyocytes were then preconditioned by exposure to transient simulated ischemia or via the administration of preconditioning mimetics (100 microM adenosine, 100 microM diazoxide and 0.5 ng ml(-1) TNFalpha, individually and in combination) prior to index ischemia. To evaluate the effect of cardiac myocyte depletion of STAT-3 in the context of the intact heart, these experiments were performed in isolated perfused Langendorff heart preparations which were exposed to an index insult of 30-min global ischemia and 45-min reperfusion. Ischemic preconditioning was achieved by subjecting the hearts to four cycles of 5-min ischemia followed by 5-min reperfusion prior to index ischemia. Infarct size was measured following reperfusion. Results Cell viability was diminished equally in wild-type and STAT-3-depleted cardiomyocytes. In contrast, ischemic and pharmacological preconditioning protected wild-type cardiomyocytes but not STAT-3-deficient cardiomyocytes. These results were mirrored in the intact heart. Conclusion The depletion of functional STAT-3 does not modulate toleranc…
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In cardiomyocyte-targeted STAT3-KO mice, cardiac STAT3 depletion does not affect infarct size, but STAT3 is crucial for cardiac preconditioning.
“Studies with cardiomyocyte-targeted STAT3-KO mice reveal that although cardiac STAT3 depletion did not affect infarct size, STAT3 is crucial for cardiac preconditioning (Smith et al., 2004).”
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 Smith et al., 2004
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Takeda, K., Kaisho, T., Yoshida, N., Takeda, J., Kishimoto, T., & Akira, S. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.9.4652 · Cited by 584 · see citing works
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“Studies with cardiomyocytetargeted STAT3-KO mice reveal that although cardiac STAT3 depletion did not affect infarct size, STAT3 is crucial for cardiac preconditioning (Smith et al., 2004).”
BackgroundMolecular Mechanisms in Heart Failure
Hilfiker-Kleiner, D., Landmesser, U., & Drexler, H. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2006.07.007 · Cited by 151 · see citing works
Szczepanek, K., Chen, Q., Larner, A. C., & Lesnefsky, E. J. (2012) · Mitochondrion · doi:10.1016/j.mito.2011.08.011 · Cited by 117 · see citing works
Many good reasons to have STAT3 in the heart
Hilfiker-Kleiner, D., Hilfiker, A., & Drexler, H. (2005) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.02.003 · Cited by 115 · see citing works
Nuclear-encoded mitochondrial proteins and their role in cardioprotection
Boengler, K., Heusch, G., & Schulz, R. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.01.009 · Cited by 68 · see citing works
- Authors
- SMITH, R., SULEMAN, N., LACERDA, L., OPIE, L., AKIRA, S., CHIEN, K., & SACK, M.
- Affiliations
- University of Cape Town (ZA)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- University of California San Diego (US)
- National Institutes of Health (US)
- Corresponding author
- SMITH, R
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-09-01
- Volume
- 63
- Issue
- 4
- Pages
- 611-616
- ISSN
- 0008-6363 (ISSN-L)
- OpenAlex
- W2009316212
- Cited by
- 128
- References
- 1
- Citations by year
- 2024: 3 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 8 · 2015: 6 · 2014: 8 · 2013: 6 · 2012: 10
- FWCI
- 5.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Health Sciences › Medicine › Emergency Medicine › Cardiac Arrest and Resuscitation
- Keywords
- STAT3, ischemic preconditioning, cardiomyocytes, ischemic tolerance, global cerebral ischemia, ischemia-reperfusion injury, infarct size, adenosine, diazoxide, TNF-α, gene deletion
- MeSH terms
- Animals, DNA-Binding Proteins, Perfusion, Trans-Activators, Myocardial Ischemia, Mice, Knockout, Ischemic Preconditioning, Myocardial, Myocytes, Cardiac, STAT3 Transcription Factor, Mice
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