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A mechanistic role for cardiac myocyte apoptosis in heart failure
Open accessAbstract
Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80-250 myocytes per 10(5) nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis. Using transgenic mice that express a conditionally active caspase exclusively in the myocardium, we demonstrate that very low levels of myocyte apoptosis (23 myocytes per 10(5) nuclei, compared with 1.5 myocytes per 10(5) nuclei in controls) are sufficient to cause a lethal, dilated cardiomyopathy. Interestingly, these levels are four- to tenfold lower than those observed in failing human hearts. Conversely, inhibition of cardiac myocyte death in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, the hallmarks of heart failure. To our knowledge, these data provide the first direct evidence that myocyte apoptosis may be a causal mechanism of heart failure, and they suggest that inhibition of this cell death process may constitute the basis for novel therapies.
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“Accordingly, inhibiting caspases can both reduce the occurrence of heart failure or slow its progression after MI (45, 131, 374, 383, 384) as well as improve contractile function (45).”
From Cardiac remodeling in obesity (2008) · cites this paper as [374]
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Metadata
- Authors
- Wencker, D., Chandra, M., Nguyen, K., Miao, W., Garantziotis, S., Factor, S. M., Shirani, J., Armstrong, R. C., & Kitsis, R. N.
- Affiliations
- Albert Einstein College of Medicine (US)
- Yeshiva University (US)
- Pfizer (United States) (US)
- Corresponding author
- Kitsis, Richard N.
- Venue
- Journal of Clinical Investigation
- Published
- 2003-05-15
- Volume
- 111
- Issue
- 10
- Pages
- 1497-1504
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC155051
- OpenAlex
- W2002958873
- Cited by
- 765
- References
- 29
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 27 · 2023: 18 · 2022: 31 · 2021: 18 · 2020: 31 · 2019: 23 · 2018: 28 · 2017: 32 · 2016: 35 · 2015: 28 · 2014: 45 · 2013: 30 · 2012: 42
- FWCI
- 32.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ariad Pharmaceuticals
- New York Academy of Medicine
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01-HL-61550, R01 HL-60665, R01HL061550, R01HL060665)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- cardiomyocyte apoptosis, heart failure, dilated cardiomyopathy, caspases, transgenic mice, myocardial cell death, contractile dysfunction, heart failure pathogenesis
- MeSH terms
- Animals, Disease Models, Animal, Enzyme Activation, Heart Failure, Humans, Mice, Inbred C57BL, Mice, Transgenic, Myocardium, Organ Specificity, Recombinant Fusion Proteins, Tacrolimus, Apoptosis, Disease Progression, Transgenes, Dimerization, Caspases, Enzyme Activators, Tacrolimus Binding Proteins, Myocytes, Cardiac, Mice, Caspase 8, Caspase 9
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