The mitochondrial apoptotic pathway is activated by serum and glucose deprivation in cardiac myocytes

Shani Bialik, Vincent L. Cryns, Andjela Drincic, Setsuya Miyata, Adam L. Wollowick, Anu Srinivasan, Richard N. Kitsis

Research output: Contribution to journalArticlepeer-review

228 Scopus citations

Abstract

Many cell types undergo apoptosis under conditions of ischemia. Little is known, however, about the molecular pathways that mediate this response. A cellular and biochemical approach to elucidate such signaling pathways was undertaken in primary cultures of cardiac myocytes, a cell type that is especially sensitive to ischemia-induced apoptosis. Deprivation of serum and glucose, components of ischemia in vivo, resulted in myocyte apoptosis, as determined by nuclear fragmentation, internucleosomal cleavage of DNA, and processing of caspase substrates. These manifestations of apoptosis were blocked by zVAD-fmk, a peptide caspase inhibitor, indicating that caspase activity is necessary for the progression of apoptosis in this model. In contrast to control cells, apoptotic myocytes exhibited cytoplasmic accumulation of cytochrome c, indicating release from the mitochondria. Furthermore, both caspase-9 and caspase-3 were processed to their active forms in serum-/glucose-deprived myocytes. Caspase processing, but not cytochrome c release, was inhibited by zVAD-fmk, placing the latter event upstream of caspase activation. This evidence demonstrates that components of ischemia activate the mitochondrial death pathway in cardiac myocytes.

Original languageEnglish (US)
Pages (from-to)403-414
Number of pages12
JournalCirculation Research
Volume85
Issue number5
DOIs
StatePublished - Sep 3 1999

Keywords

  • Apoptosis
  • Cysteine proteinase
  • Cytochrome c
  • Ischemia
  • Mitochondria

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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