The Fas receptor - 1,4,5-IP3 cascade: A potential target for treating heart failure and arrhythmias

Ofer Binah, Mark Shilkrut, Gal Yaniv, Sarit Larisch

Research output: Contribution to journalArticlepeer-review


Activation of the Fas receptor in various cell types, including myocytes, triggers apoptotic as well as nonapoptotic effects. Recent studies suggest that Fas activation in the heart participates in the development of major pathologies such as myocarditis and ischemic/reperfusion insults, which are manifested by arrhythmias and mechanical dysfunction. To decipher the contribution of the Fas/FasL pathway to myocardial pathologies, we have investigated the functional consequences of Fas activation in normoxic and hyporic ventricular myocytes. Our major findings were as follows. (1) Although Fas is constitutively expressed in ventricular myocytes, normoxic myocytes are resistant to Fas-mediated apoptosis. In contrast, hypoxia predisposes myocytes to apoptosis induced by Fas activation. The underlying mechanism is a shift in the balance between proapoptotic proteins (including Fas) and antiapoptotic proteins toward the former. (2) In normoxic myocytes, Fas activation causes a wide range of functional disturbances, which include reduction in resting potential and action potential amplitude, prolonged action potential duration, development of delayed and early after-depolarizations, occasionally culminating into arrhythmias, diastolic [Ca2+]i level increase, decreased Ito and increased ICa,L. (3) The above-mentioned effects in normoxic myocytes (but not Fas-mediated apoptosis in hypoxic myocytes) depend on the phospholipase C → 1,4,5-IP3 → SR [Ca 2+]i release cascade. (4) Inhibition of tyrosine kinases with genistein blocks both the apoptotic and nonapoptotic consequences of Fas activation in ventricular myocytes. Based on these studies we propose that tyrosine phosphorylation in ventricular myocytes can serve as a novel potential target for attenuating Fas-mediated dysfunction in normoxic and hypoxic myocardium.

Original languageEnglish
Pages (from-to)338-350
Number of pages13
JournalAnnals of the New York Academy of Sciences
StatePublished - 2004
Externally publishedYes


  • 1,4,5-IP
  • Apoptosis
  • Arrhythmias
  • Fas receptor
  • Heart failure
  • Hypoxia
  • Ventricular myocytes

ASJC Scopus subject areas

  • Neuroscience (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • History and Philosophy of Science


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