Circulation Research. 2003;92:715-724
Published online before print March 20, 2003, doi: 10.1161/01.RES.0000067471.95890.5C
Published online before print March 20, 2003, doi: 10.1161/01.RES.0000067471.95890.5C
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© 2003 American Heart Association, Inc.
Molecular Medicine |
Myocytes Die by Multiple Mechanisms in Failing Human Hearts
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.
Correspondence to Sawa Kostin, MD, Max-Planck-Institute, Department of Experimental Cardiology, Benekestr 2D-61231 Bad Nauheim, Germany. E-mail skostin{at}kerckhoff.mpg.de
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.
Key Words: cell death • oncosis • apoptosis • autophagy • ubiquitin
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