Chelerythrine rapidly induces apoptosis through generation of reactive oxygen species in cardiac myocytes

Shimako Yamamoto, Koichi Seta, Carmine Morisco, Stephen F. Vatner, Junichi Sadoshima

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

The role of protein kinase C (PKC) inhibition in cardiac myocyte apoptosis has not been well understood. We investigated the mechanism, by which chelerythrine, a commonly used PKC inhibitor, induces potent myocyte death, Chelerythrine (6-30 μM) rapidly induced pyknosis, shrinkage and subsequent cell death in cardiac myocytes. Chelerythrine-induced myocyte death was accompanied by nuclear fragmentation and activation of caspase-3 and -9, while it was prevented by XIAP, suggesting that the cell death is due to apoptosis. Higher concentrations of chelerythrine caused necrotic cell death where neither cell shrinkage nor caspase activation was observed. Intravenous injection of chelerythrine (5 mg/kg) also increased apoptosis in adult rat hearts in vivo. Downregulation of the phorbol 12-myristate 13-acetate (PMA)-sensitive PKC failed to affect chelerythrine-induced apoptosis, while anti-oxidants, including N-acetyl-L-cysteine (NAC) and glutathione, inhibited it, suggesting that generation of reactive oxygen species (ROS) rather than inhibition of PMA-sensitive PKC mediates chelerythrine-induced cardiac myocyte apoptosis. Chelerythrine caused cytochrome c release from mitochondria, which was significantly inhibited in the presence of NAC, suggesting that ROS mediates chelerythrine-induced cytochrome c release. Partial inhibition of cytochrome c release by Bcl-XL significantly reduced chelerythrine-induced apoptosis. These results suggest that chelerythrine rapidly induces cardiac myocyte apoptosis and that production of ROS, possibly H2O2, and subsequent cytochrome c release from mitochondria play an important role in mediating chelerythrine-induced rapid cardiac myocyte apoptosis.

Original languageEnglish (US)
Pages (from-to)1829-1848
Number of pages20
JournalJournal of Molecular and Cellular Cardiology
Volume33
Issue number10
DOIs
StatePublished - 2001

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Keywords

  • Apoptosis
  • Cardiac myocytes
  • Oxidative stress
  • Protein kinase C

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