title: 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< or =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.
authors.affiliation: Max-Planck-Institute, Department of Experimental Cardiology, Benekestr 2D-61231 Bad Nauheim, Germany. skostin@kerckhoff.mpg.de
authors.forename: Sawa
authors.initials: S
authors.lastname: Kostin
authors.forename: Lieven
authors.initials: L
authors.lastname: Pool
authors.forename: Albrecht
authors.initials: A
authors.lastname: Elsässer
authors.forename: Stefan
authors.initials: S
authors.lastname: Hein
authors.forename: Hannes C A
authors.initials: HC
authors.lastname: Drexler
authors.forename: Eyal
authors.initials: E
authors.lastname: Arnon
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: René
authors.initials: R
authors.lastname: Zimmermann
authors.forename: Erwin
authors.initials: E
authors.lastname: Bauer
authors.forename: Wolf-Peter
authors.initials: WP
authors.lastname: Klövekorn
authors.forename: Jutta
authors.initials: J
authors.lastname: Schaper
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D019759:Carbon-Nitrogen Lyases / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000473:pathology*; D002402:Cathepsin D / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D008025:Ligases / Q000378:metabolism; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D009097:Multienzyme Complexes / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009336:Necrosis; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases
chemical_list: D009097:Multienzyme Complexes; D025801:Ubiquitin; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D003546:Cysteine Endopeptidases; D002402:Cathepsin D; D046988:Proteasome Endopeptidase Complex; D019759:Carbon-Nitrogen Lyases; C034300:isopeptidase; D008025:Ligases; D044764:Ubiquitin-Activating Enzymes