Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes

doi:10.1016/S0008-6363(02)00646-6

Cardiovascular Research 2003 57(1):119-128; doi:10.1016/S0008-6363(02)00646-6
© 2003 by European Society of Cardiology

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Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes

Joji Nitobe^a^,*, Seiji Yamaguchi^a, Masaki Okuyama^a, Naoki Nozaki^a, Masataka Sata^b, Takuya Miyamoto^a, Yasuchika Takeishi^a, Isao Kubota^a and Hitonobu Tomoike^a

^aFirst Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan
^bDepartment of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan

^* Corresponding author. Tel.: +81-23-628-5302; fax: +81-23-628-5305. jnitobe{at}med.id.yamagata-u.ac.jp

Objective: Fas ligand (FasL) is a key cytokine which initiatesapoptosis when FasL binds to its receptor, Fas. Cardiac myocytesare generally resistant to Fas-induced apoptosis. However, sublethaldose of doxorubicin (Dox) can sensitize cardiac myocytes toFas-induced apoptosis. We investigated the molecular mechanismby which Dox sensitizes cardiac myocytes to Fas-induced apoptosis.FLICE inhibitory protein (FLIP) is a key molecule for blockingFas-induced apoptosis by functioning as a caspase-8 dominantnegative. Methods and results: FLIP was constitutively expressedin cultured neonatal rat cardiac myocytes. FLIP protein levelswere markedly down-regulated by Dox in a time-dependent anddose-dependent manner. Next, we examined the relation of reactiveoxygen species (ROS) by Dox to the expression of FLIP. Bothof N-acetylcysteine (NAC) and the combination of superoxidedismutase and catalase restored the decreased FLIP in Dox-treatedcardiac myocytes to the basal level. NAC also restored the increasedformation of thiobarbituric acid-reactive substance after Dox-treatment.Concurrently, the susceptibility to Fas-mediated apoptosis disappearedwith the treatments of the antioxidant agents. Hydrogen peroxidedown-regulated FLIP in a dose-dependent fashion and also sensitizedcardiac myocytes to Fas-induced apoptosis. Conclusions: FLIP,an inhibitor of apoptosis induced by cytokines of TNF family,contributes at least partly to Dox-induced sensitization toFas-mediated apoptosis in cardiac myocytes. The expression ofFLIP in cardiac myocytes is regulated by ROS.

KEYWORDS Apoptosis; Cardiomyopathy; Cytokines; Free radicals; Myocytes

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