Cardiac endothelial cells regulate reactive oxygen species-induced cardiomyocyte apoptosis through neuregulin-1beta/erbB4 signaling.

Kuramochi Y, Cote GM, Guo X, Lebrasseur NK, Cui L, Liao R, Sawyer DB
J Biol Chem. 2004 279 (49): 51141-7

PMID: 15385548 · DOI:10.1074/jbc.M408662200

Neuregulin (NRG)-1beta has a prosurvival effect on cardiac myocytes via the phosphatidylinositol-3-kinase/Akt pathway, but the physiological regulators of this system in the intact heart are unknown. In this study, we tested the hypothesis that reactive oxygen species regulate NRG/erbB signaling. We used isolated adult rat ventricular myocytes (ARVMs) or cardiac microvascular endothelial cells (CMECs) in monoculture, or together in coculture. H2O2 induced NRG-1beta release from CMECs in a concentration-dependent manner, and conditioned medium from H2O2-treated CMEC activated ARVM erbB4. NRG-1beta release occurred via proteolytic cleavage of 115-kDa transmembrane NRG-1beta and was inhibited by the metalloproteinase inhibitor 1,10-phenanthroline. In myocyte monoculture, H2O2 induced erbB4-dependent, but NRG-independent, activation of Akt. To elucidate the bioactivity of CMEC-derived NRG-1beta on ARVMs, we examined H2O2-induced myocyte apoptosis in co-culture using an antibody to NRG-1beta. The percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were significantly higher in the anti-NRG-1beta group than in the control group. The change in apoptosis induced by anti-NRG-1beta in co-culture was similar in magnitude to the protection of myocytes by addition of recombinant NRG-1beta to ARVM monocultures. Activation of NRG/erbB paracrine signaling was also seen in the intact heart subjected to oxidative stress by ischemia-reperfusion injury. Isolated perfused mouse hearts subjected to 15 min of ischemia, followed by 30 min of reperfusion, showed complete proteolytic cleavage of 115-kDa NRG-1beta, with concomitant erbB4 phosphorylation. These results demonstrate that reactive oxygen species activate NRG-1beta/erbB4 paracrine signaling in the heart and suggest that this system is involved in cardiac adaptation to oxidative stress.

MeSH Terms (32)

Animals Apoptosis Blotting, Western Cells, Cultured Cell Survival Coculture Techniques Cross-Linking Reagents Culture Media, Conditioned Dose-Response Relationship, Drug Endothelium, Vascular Enzyme Activation Humans Hydrogen Peroxide Immunoblotting Immunoprecipitation In Situ Nick-End Labeling Mice Microcirculation Myocardium Neuregulin-1 Perfusion Phenanthrolines Phosphatidylinositol 3-Kinases Protein-Serine-Threonine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt Rats Reactive Oxygen Species Recombinant Proteins Reperfusion Injury Signal Transduction Time Factors

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