© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Hypoxia predisposes neonatal rat ventricular myocytes to apoptosis induced by activation of the Fas (CD95/Apo-1) receptor: Fas activation and apoptosis in hypoxic myocytes
aBruce Rappaport Faculty of Medicine, The Bernard Katz Minerva Center for Cell Biophysics, Technion–Israel Institute of Technology, Haifa, Israel
bDepartment of Pathology, Rambam Medical Center, Haifa, Israel
cDepartment of Immunology, Weizmann Institute, Rehovot, Israel
* Corresponding author. Present address: Cardiac Research Laboratory, Floor 9 (POB 9697), Rappaport Institute, Efron Street, Bat-Galim, Haifa 31096, Israel. Tel.: +972-4-829-5262; fax: +972-4-851-3919 binah{at}tx.technion.ac.il
Objective: Since apoptosis is an important contributor to heart diseases in which ischemia and hypoxia are key elements, we tested the hypothesis that hypoxia predisposes neonatal rat ventricular myocytes (NRVM) to Fas-mediated apoptosis, by shifting the balance between antiapoptotic and proapoptotic proteins towards the latter. Methods: Normoxic or hypoxic (22 h, 1% O2) cultured NRVM were exposed to recombinant Fas L (rFasL) for 7 h, and apoptosis measured thereafter. Results: Whereas in normoxic NRVM, rFasL did not cause apoptosis measured by the TUNEL assay (4.8±0.5% in control versus 4.5±0.9% in rFasL), in hypoxic cultures rFasL increased the background apoptosis level by 100%. That Fas was functional in normoxic NRVM, despite its inability to mediate apoptosis, was evidenced by the finding that Fas activation increased the diastolic [Ca2+]i levels measured by Fura 2 fluorescence, and caused arrhythmias. In support of our working hypothesis, hypoxia increased Fas expression by 200% (measured by quantitative Western blot), and the expression of the proapoptotic proteins ARTS and FADD by 323 and 250%, respectively, and decreased the expression of the antiapoptotic proteins ARC and FLIP by 90 and 60%, respectively. Conclusion: By upregulating Fas expression and key proapoptotic proteins, and by downregulating antiapoptotic proteins, hypoxia predisposes ventricular myocytes to Fas-induced apoptosis.
KEYWORDS Apoptosis; Calcium (cellular); Hypoxia/anoxia; Ischemia; Myocytes
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