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H(2)O(2) regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathways
Susan H Kwon1, David R Pimentel, Andrea Remondino
1Myocardial Biology Unit and Cardiovascular Division, Boston University Medical Center, and School of Medicine, 88 East Newton Street, MA 02118, Boston, USA.
Abstract:
Reactive oxygen species (ROS) can act as signaling molecules to stimulate either hypertrophy or apoptosis in cardiac myocytes. We tested the hypothesis that the phenotypic effects of ROS are due to differential, concentration-dependent activation of specific kinase signaling pathways. Adult rat ventricular myocytes were exposed to H(2)O(2) over a broad concentration range (10-1000 microM). Low concentrations of H(2)O(2) (10-30 microM) increased protein synthesis without affecting survival. Higher concentrations of H(2)O(2) (100-200 microM) increased apoptosis (assessed by TUNEL). Still higher concentrations of H(2)O(2) (300-1000 microM) caused both apoptosis and necrosis. A hypertrophic concentration of H(2)O(2) (10 microM) increased the activity of ERK1/2, but not that of JNK, p38 kinase or Akt. An apoptotic concentration of H(2)O(2) (100 microM) activated JNK, p38 kinase and Akt, and further activated ERK1/2. The MEK1/2 inhibitor U0126 prevented the hypertrophic effect of 10 microM H(2)O(2). The apoptotic effect of 100 microM H(2)O(2) was inhibited bya dominant-negative JNK adenovirus, and was potentiated by U0126 or an Akt inhibitor. Thus, the concentration-dependent effects of ROS on myocyte hypertrophy and growth are due, at least in part, to the differential activation of specific kinase signaling pathways that regulate hypertrophy and apoptosis.
Insights
Reactive oxygen species (ROS) trigger cardiac myocyte hypertrophy or apoptosis based on concentration. Differential kinase pathway activation explains these ROS effects, revealing distinct signaling for growth versus cell death.
Area of Science:
- Cardiovascular Biology
- Cell Signaling
- Oxidative Stress
Background:
- Reactive oxygen species (ROS) are crucial signaling molecules in cardiac myocytes.
- ROS can induce either cardiac myocyte hypertrophy (growth) or apoptosis (programmed cell death).
Purpose of the Study:
- To investigate if concentration-dependent ROS effects on cardiac myocytes are mediated by specific kinase signaling pathways.
- To elucidate the role of differential kinase activation in ROS-induced hypertrophy and apoptosis.
Main Methods:
- Adult rat ventricular myocytes were treated with hydrogen peroxide (H2O2) across a wide concentration range (10-1000 microM).
- Kinase activity (ERK1/2, JNK, p38, Akt) was measured.
- Specific inhibitors (U0126, dominant-negative JNK, Akt inhibitor) were used to block signaling pathways.
Main Results:
- Low H2O2 concentrations (10-30 microM) promoted protein synthesis (hypertrophy) via ERK1/2 activation.
- Higher H2O2 concentrations (100-200 microM) induced apoptosis through JNK, p38, and Akt activation.
- Inhibitor studies confirmed the roles of ERK1/2 in hypertrophy and JNK/p38/Akt in apoptosis.
Conclusions:
- ROS exert concentration-dependent effects on cardiac myocytes, driving either hypertrophy or apoptosis.
- Differential activation of specific kinase pathways (ERK1/2, JNK, p38, Akt) underlies these distinct cellular responses.
- Targeting these kinase pathways could modulate ROS-induced cardiac myocyte remodeling.
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