Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis.
BACKGROUND
The importance of free radical homeostasis and apoptosis in normal and diseased hearts and their interrelationships are poorly defined. We tested whether reactive oxygen species can trigger apoptosis in cardiomyocytes, and we explored the underlying pathways.


RESULTS
A cell culture model of isolated cardiac cells and different reactive oxygen species (ROS)-generating systems were used. Apoptosis became evident when cardiomyocytes were exposed to either H2O2 or superoxide anion (O2-). Both H2O2- and O2--induced apoptosis of cardiomyocytes were associated with an increase in p53 protein content, whereas protein levels of Bax and Bcl-2 were unaltered. H2O2, but not O2-, induced an increase in the protein content of Bad. Furthermore, H2O2 elicited translocation of Bax and Bad from cytosol to mitochondria, where these factors formed heterodimers with Bcl-2, which was followed by the release of cytochrome c, activation of CPP32, and cleavage of poly(ADP-ribose) polymerase. Interestingly, this pathway was not activated by O2-. Instead, O2- used Mch2alpha to promote the apoptotic pathway, as revealed by the activation of Mch2alpha and the cleavage of its substrate, lamin A.


CONCLUSIONS
Taken together, these results indicate that ROS may play an important pathophysiological role in cardiac diseases characterized by apoptotic cell death and suggest that different ROS-induced activations of the apoptotic cell death program in cardiomyocytes involve distinct signaling pathways.
von Harsdorf
R
R
Department of Cardiology, Franz Volhard Clinic, Humboldt-University, Berlin, Germany. rharsdo@mdc-berlin.de
Li
P F
PF
Dietz
R
R
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein
C494821:Bad protein, rat; C494828:Bax protein, rat; D002352:Carrier Proteins; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D006861:Hydrogen Peroxide; D020169:Caspases; D010100:Oxygen