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The Fas Receptor—1,4,5‐IP 3 Cascade: A Potential Target for Treating Heart Failure and Arrhythmias
Author(s) -
BINAH OFER,
SHILKRUT MARK,
YANIV GAL,
LARISCH SARIT
Publication year - 2004
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1302.030
Subject(s) - myocyte , fas ligand , apoptosis , medicine , endocrinology , chemistry , microbiology and biotechnology , programmed cell death , biology , biochemistry
A bstract : 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 hypoxic 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 [Ca 2+ ] i level increase, decreased I to and increased I Ca,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‐IP 3 → 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.