Abstract
Recombinant human neuregulin-1 (rhNRG-1) improves cardiac function in animal models of doxorubicin (DOX)-induced cardiomyopathy, but the underlying mechanism remains largely unknown. Here, we confirm a role for rhNRG-1 in attenuating DOX-induced autophagy and define the signaling pathways through which it mediates some of its effects. Neonatal rat ventricular myocytes were subjected to different treatments both to induce autophagy and to determine the effects of rhNRG-1 on the process. The rhNRG-1 inhibited DOX-induced autophagy, reduced reactive oxygen species production and increased protein expression of Bcl-2, effects that were recapitulated when the cells were treated with the antioxidant N-acetylcysteine. These effects were blocked by the phosphatidylinositol 3-kinase inhibitor LY294002, pointing to the involvement of the Akt pathway in mediating the process. Inhibition of Bcl-2 expression with small interfering RNA silencing also inhibited rhNRG-1's ability to attenuate DOX-induced autophagy. The rhNRG-1 is a potent inhibitor of DOX-induced autophagy and multiple signaling pathways, including Akt and activation of reactive oxygen species, play important roles in the anti-autophagy effect. The rhNRG-1 is a novel drug that may be effectively therapeutically in protecting further damage in DOX-induced damaged myocardium.
MeSH terms
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Animals
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Animals, Newborn
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Antibiotics, Antineoplastic / adverse effects
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Antibiotics, Antineoplastic / antagonists & inhibitors*
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Antioxidants / pharmacology
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Autophagy / drug effects*
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Cardiomyopathies / chemically induced
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Cardiomyopathies / prevention & control
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Cardiotonic Agents / pharmacology*
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Cells, Cultured
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Doxorubicin / adverse effects
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Doxorubicin / antagonists & inhibitors*
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Enzyme Inhibitors / pharmacology
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Humans
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / drug effects*
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Myocytes, Cardiac / metabolism
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Neuregulin-1 / genetics
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Neuregulin-1 / pharmacology*
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Oxidative Stress / drug effects
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Phosphatidylinositol 3-Kinase / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism
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Recombinant Proteins / pharmacology*
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Signal Transduction / drug effects
Substances
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Antibiotics, Antineoplastic
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Antioxidants
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Cardiotonic Agents
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Enzyme Inhibitors
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NRG1 protein, human
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Neuregulin-1
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Reactive Oxygen Species
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Recombinant Proteins
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Doxorubicin
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Phosphatidylinositol 3-Kinase
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Akt1 protein, rat
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Proto-Oncogene Proteins c-akt