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Published on: July 13, 2018
Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis
R von Harsdorf1, P F Li, R Dietz
1Department of Cardiology, Franz Volhard Clinic, Humboldt-University, Berlin, Germany. rharsdo@mdc-berlin.de
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.
Methods And 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.
Insights
Reactive oxygen species (ROS) trigger apoptosis in heart cells via distinct pathways. Hydrogen peroxide activates the intrinsic pathway, while superoxide anion utilizes a different route involving Mch2alpha, highlighting ROS
Area of Science:
- Cardiovascular Biology
- Cellular Signaling
- Oxidative Stress Research
Background:
- The interplay between free radical homeostasis, apoptosis, and cardiac health is not well understood.
- Investigating the role of reactive oxygen species (ROS) in cardiomyocyte apoptosis is crucial for understanding cardiac diseases.
Purpose of the Study:
- To determine if ROS can induce apoptosis in cardiomyocytes.
- To elucidate the specific molecular pathways involved in ROS-mediated cardiomyocyte apoptosis.
Main Methods:
- Utilized an isolated cardiac cell culture model.
- Employed various ROS-generating systems (H2O2, superoxide anion).
- Analyzed protein expression (p53, Bax, Bcl-2, Bad), protein translocation, and enzyme activation (CPP32, Mch2alpha).
Main Results:
- Both H2O2 and superoxide anion induced cardiomyocyte apoptosis.
- H2O2-induced apoptosis involved p53, Bax, Bad translocation, cytochrome c release, and CPP32 activation.
- Superoxide anion-induced apoptosis utilized Mch2alpha activation and lamin A cleavage, distinct from the H2O2 pathway.
Conclusions:
- ROS play a significant role in the pathophysiology of cardiac diseases involving apoptotic cell death.
- Distinct ROS trigger cardiomyocyte apoptosis through separate signaling cascades, offering potential therapeutic targets.
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