Myocytes Die by Multiple Mechanisms in Failing Human Hearts
Abstract
We tested the hypothesis that myocyte loss in failing human hearts occurs by different mechanisms: apoptosis, oncosis, and autophagic cell death. Explanted hearts from 19 patients with idiopathic dilated cardiomyopathy (EF≤20%) and 7 control hearts were analyzed. Myocyte apoptosis revealed by caspase-3 activation and TUNEL staining occurred at a rate of 0.002±0.0005% ( P <0.05 versus control) and oncosis assessed by complement 9 labeling at 0.06±0.001% ( P <0.05). Cellular degeneration including appearance of ubiquitin containing autophagic vacuoles and nuclear disintegration was present at the ultrastructural level. Nuclear and cytosolic ubiquitin/protein accumulations occurred at 0.08±0.004% ( P <0.05). The ubiquitin-activating enzyme E1 and the ligase E3 were not different from control. In contrast, ubiquitin mRNA levels were 1.8-fold ( P <0.02) elevated, and the conjugating enzyme E2 was 2.3-fold upregulated ( P <0.005). The most important finding, however, is the 2.3-fold downregulation of the deubiquitination enzyme isopeptidase-T and the 1.5-fold reduction of the ubiquitin-fusion degradation system-1, which in conjunction with unchanged proteasomal subunit levels and proteasomal activity results in massive storage of ubiquitin/protein complexes and in autophagic cell death. A 2-fold decrease of cathepsin D might be an additional factor responsible for the accumulation of ubiquitin/protein conjugates. It is concluded that in human failing hearts apoptosis, oncosis, and autophagy act in parallel to varying degrees. A disturbed balance between a high rate of ubiquitination and inadequate degradation of ubiquitin/protein conjugates may contribute to autophagic cell death. Together, these different types of cell death play a significant role for myocyte disappearance and the development of contractile dysfunction in failing hearts.
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It is possible to use anti-LC3/Atg8 antibodies for immunocytochemistry or immunohistochemistry, procedures that have the advantages of detecting the endogenous protein, obviating the need for transfection and/or the generation of a transgenic organism, as well as avoiding potential artifacts resulting from overexpression.
“It is also possible to use anti-LC3/Atg8 antibodies for immunocytochemistry or immunohistochemistry, 140,[204][205][206][207][208][209] procedures that have the advantages of detecting the endogenous protein, obviating the need for transfection and or the generation of a transgenic organism, as well as avoiding potential artifacts resulting from overexpression”
From Guidelines for the use and interpretation of assays for monitoring autophagy (2012) · cites this paper as [205]
Myocyte apoptosis has been suggested to be an important etiological component of heart failure, particularly in the transition from compensatory remodeling to heart failure, although this concept has been somewhat contentious.
“Myocyte apoptosis has been suggested to be an important etiological component of heart failure, particularly in the transition from compensatory remodeling to heart failure (112), although this concept has been somewhat contentious (95, 189, 295, 301).”
From Cardiac remodeling in obesity (2008) · cites this paper as [189]
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“Excessive autophagy under stress was responsible for cardiac remodeling [22,23].”
- Authors
- Kostin, S., Pool, L., Elsässer, A., Hein, S., Drexler, H. C. A., Arnon, E., Hayakawa, Y., Zimmermann, R., Bauer, E., Klövekorn, W.-P., & Schaper, J.
- Affiliations
- From the Departments of Experimental Cardiology (S.K., L.P., E.A., Y.H., J.S.) and Molecular Cell Biology (H.C.A.D.), Max-Planck-Institute, Bad Nauheim, Germany; Departments of Cardiac Surgery (S.H., R.Z., E.B., W.-P.K.) and Vascular Genomics (R.Z.), Kerckhoff-Clinic, Bad Nauheim, Germany; and the Department of Cardiology (A.E.), University of Freiburg, Germany.
- University of Freiburg (DE)
- Venue
- Circulation Research
- Published
- 2003-04-18
- Volume
- 92
- Issue
- 7
- Pages
- 715-724
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2151582019
- Cited by
- 564
- References
- 44
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 11 · 2023: 15 · 2022: 21 · 2021: 27 · 2020: 24 · 2019: 14 · 2018: 21 · 2017: 36 · 2016: 29 · 2015: 21 · 2014: 27 · 2013: 35 · 2012: 40
- FWCI
- 9.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- cardiomyocyte death, heart failure, idiopathic dilated cardiomyopathy, apoptosis, oncosis, autophagic cell death, ubiquitin conjugates, cathepsin D, caspase-3, ubiquitination, proteasome, contractile dysfunction
- MeSH terms
- Autophagy, Cardiomyopathy, Dilated, Cathepsin D, Cysteine Endopeptidases, Humans, Ligases, Multienzyme Complexes, Necrosis, Blotting, Western, Microscopy, Immunoelectron, Apoptosis, Microscopy, Confocal, Carbon-Nitrogen Lyases, In Situ Nick-End Labeling, Ubiquitin, Myocytes, Cardiac, Ubiquitin-Conjugating Enzymes, Ubiquitin-Activating Enzymes, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex
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