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

Yukio Kuramochi, Gregory M. Cote, Xinxin Guo, Nathan K. Lebrasseur, Lei Cui, Ronglih Liao, Douglas B. Sawyer

Research output: Contribution to journalArticlepeer-review

144 Scopus citations


Neuregulin (NRG)-1β 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 co-culture. H 2O2 induced NRG-1β release from CMECs in a concentration-dependent manner, and conditioned medium from H2O 2-treated CMEC activated ARVM erbB4. NRG-1β release occurred via proteolytic cleavage of 115-kDa transmembrane NRG-1β 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-1β on ARVMs, we examined H2O2-induced myocyte apoptosis in co-culture using an antibody to NRG-1β. The percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were significantly higher in the anti-NRG-1β group than in the control group. The change in apoptosis induced by anti-NRG-1β in co-culture was similar in magnitude to the protection of myocytes by addition of recombinant NRG-1β 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-1β, with concomitant erbB4 phosphorylation. These results demonstrate that reactive oxygen species activate NRG-1β/erbB4 paracrine signaling in the heart and suggest that this system is involved in cardiac adaptation to oxidative stress.

Original languageEnglish (US)
Pages (from-to)51141-51147
Number of pages7
JournalJournal of Biological Chemistry
Issue number49
StatePublished - Dec 3 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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