Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury
Abstract
The transcription factor signal transducer and activator of transcription 3 (STAT3) participates in a wide variety of physiological processes and directs seemingly contradictory responses such as proliferation and apoptosis. To elucidate its role in the heart, we generated mice harboring a cardiomyocyte-restricted knockout of STAT3 using Cre/loxP-mediated recombination. STAT3-deficient mice developed reduced myocardial capillary density and increased interstitial fibrosis within the first 4 postnatal months, followed by dilated cardiomyopathy with impaired cardiac function and premature death. Conditioned medium from STAT3-deficient cardiomyocytes inhibited endothelial cell proliferation and increased fibroblast proliferation, suggesting the presence of paracrine factors attenuating angiogenesis and promoting fibrosis in vitro. STAT3-deficient mice showed enhanced susceptibility to myocardial ischemia/reperfusion injury and infarction with increased cardiac apoptosis, increased infarct sizes, and reduced cardiac function and survival. Our study establishes a novel role for STAT3 in controlling paracrine circuits in the heart essential for postnatal capillary vasculature maintenance, interstitial matrix deposition balance, and protection from ischemic injury and heart failure.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 Hilfiker-Kleiner et al., 2004
Following I/R injury, cardiomyocyte-specific STAT3-KO mice have greater infarct size and cardiomyocyte apoptosis.
“Following I/R injury (Hilfiker-Kleiner et al., 2004), cardiomyocyte-specific STAT3-KO mice had greater infarct size and cardiomyocyte apoptosis”
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 Hilfiker-Kleiner et al., 2004
Cites
YU, Z., ZHANG, W., & KONE, B. C. (2002) · Biochemical Journal · doi:10.1042/bj20020588 · Cited by 255 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Kempf, T., Eden, M., Strelau, J., Naguib, M., Willenbockel, C., Tongers, J., Heineke, J., Kotlarz, D., Xu, J., Molkentin, J. D., et al. (2006) · Circulation Research · doi:10.1161/01.res.0000202805.73038.48 · Cited by 651 · see citing works
Self-citationBharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“Following I/R injury (Hilfiker-Kleiner et al., 2004), cardiomyocyte-specific STAT3-KO mice had greater infarct size and cardiomyocyte apoptosis presumably due to increased mRNA levels of the proapoptotic and proautophagy gene, BNIP3, and decreasedmRNA levels of the prosurvival gene, heat shock…”
BackgroundSreekumar, P. G., Ishikawa, K., Spee, C., Mehta, H. H., Wan, J., Yen, K., Cohen, P., Kannan, R., & Hinton, D. R. (2016) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.15-17053 · Cited by 179 · see citing works
Molecular 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
Self-citationAleshin, 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
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
Self-citationWohlgemuth, 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
The Regenerative Activity of Interleukin-6
Galun, E., & Rose-John, S. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-308-4_4 · Cited by 34 · see citing works
- Authors
- Hilfiker-Kleiner, D., Hilfiker, A., Fuchs, M., Kaminski, K., Schaefer, A., Schieffer, B., Hillmer, A., Schmiedl, A., Ding, Z., Podewski, E., Podewski, E., Poli, V., Schneider, M. D., Schulz, R., Park, J.-K., Wollert, K. C., & Drexler, H.
- Affiliations
- From the Departments of Cardiology and Angiology (D.H.-K., A. Hilfiker, M.F., K.K., A. Schaefer, B.S., A. Hillmer, Edith Podewski, Eva Podewski, K.C.W., H.D.), Anatomy (A. Schmiedl), and Nephrology (J.-K.P.), Medical School Hannover, Germany; Institute for Cardiovascular Physiology (Z.D.), University of Düsseldorf, Germany; Department of Genetics, Biology, and Biochemistry (V.P.), University of Turin, Italy; Department of Medicine (M.D.S.), Baylor College of Medicine, Houston, Tex; Department of...
- Baylor College of Medicine (US)
- ORCID
- Venue
- Circulation Research
- Published
- 2004-07-23
- Volume
- 95
- Issue
- 2
- Pages
- 187-195
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2113162775
- Cited by
- 385
- References
- 1
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 7 · 2023: 12 · 2022: 12 · 2021: 9 · 2020: 18 · 2019: 21 · 2018: 14 · 2017: 23 · 2016: 22 · 2015: 20 · 2014: 19 · 2013: 20 · 2012: 31
- FWCI
- 11.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- STAT3, myocardial angiogenesis, capillary density, myocardial fibrosis, dilated cardiomyopathy, myocardial ischemia-reperfusion injury, cardiomyocyte apoptosis, paracrine signaling, endothelial cell proliferation, fibroblast proliferation, heart failure
- MeSH terms
- Animals, Capillaries, Cardiomyopathy, Dilated, Cell Division, Coronary Vessels, DNA-Binding Proteins, Extracellular Matrix, Fibroblasts, Fibrosis, Heart Failure, Male, Myocardium, Myocardial Reperfusion Injury, Trans-Activators, Culture Media, Conditioned, Myocardial Ischemia, Mice, Knockout, Neovascularization, Physiologic, Paracrine Communication, Genetic Predisposition to Disease, Angiogenesis Inhibitors, Myocytes, Cardiac, Endothelial Cells, STAT3 Transcription Factor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
