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Hepatocyte growth factor protects cardiac myocytes against oxidative stress-induced apoptosis
1Antioxidants Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA.
Insights
Hepatocyte growth factor (HGF) protects heart cells from oxidative stress-induced death. This cardioprotective effect involves the MEK-MAPK pathway, offering new insights into HGF
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Stress Response
Background:
- Hepatocyte growth factor (HGF) is a potential endogenous cardioprotective agent.
- The precise mechanisms of HGF action in the heart remain largely unelucidated.
Purpose of the Study:
- To investigate the protective role of HGF against oxidative stress-induced apoptosis in adult cardiac myocytes.
- To elucidate the signaling pathways involved in HGF-mediated cardioprotection.
Main Methods:
- Isolated adult rat cardiac myocytes and HL-1 cardiac muscle cells were exposed to apoptosis-inducing stimuli (daunorubicin, serum deprivation, H2O2).
- HGF treatment effects on cell viability were assessed.
- Expression and phosphorylation of c-Met receptor, and activation of MEK, p44/42 MAPK, and p90RSK were analyzed.
- The impact of a MEK inhibitor (PD98059) on HGF-mediated protection was evaluated.
Main Results:
- HGF significantly attenuated oxidative stress-induced apoptosis in cardiac myocytes at physiologically relevant concentrations.
- Cardiac myocytes express the HGF receptor, c-Met, which undergoes rapid tyrosine phosphorylation upon HGF stimulation.
- HGF activated the MEK-MAPK signaling cascade.
- Inhibition of MEK partially blocked HGF's protective effect against H2O2-induced cell death.
Conclusions:
- HGF confers protection to cardiac myocytes against oxidative stress-induced apoptosis.
- The MEK-MAPK pathway is partially involved in mediating HGF's cardioprotective signaling.
Abstract:
Hepatocyte growth factor (HGF) has been proposed as an endogenous cardioprotective agent against oxidative stress. The mechanism of HGF action in the heart, however, has not yet been elucidated. The present study demonstrates that HGF protects adult cardiac myocytes against oxidative stress-induced apoptosis. HGF, at the concentrations which can be detected in the plasma of humans subsequent to myocardial infarction, effectively attenuated death of isolated adult rat cardiac myocytes and cultured HL-1 cardiac muscle cells induced by apoptosis-inducing oxidative stress stimuli such as daunorubicin, serum deprivation, and hydrogen peroxide. We identified expression of c-Met HGF receptor in adult cardiac myocytes, which can be rapidly tyrosine phosphorylated in response to HGF treatment. HGF also activated MEK, p44/42 MAPK, and p90RSK. To determine if MEK-MAPK pathway may be involved in the mechanism of HGF-mediated cardiac myocyte protection, effects of a specific MEK inhibitor, PD98059, were studied. Pretreatment of cells with PD98059 partially blocked HGF signaling for protection against hydrogen peroxide-induced cell death. Thus, HGF protects cardiac myocytes against oxidative stress, in part, via activating MEK-MAPK pathway.