| 15482374 |
d'Anglemont de Tassigny A, Souktani R, Henry P, Ghaleh B, Berdeaux A: Volume-sensitive chloride channels (ICl,vol) mediate doxorubicin-induced apoptosis through apoptotic volume decrease in cardiomyocytes. Fundam Clin Pharmacol. 2004 Oct;18(5):531-8.
Apoptosis is associated with early changes in cell volume through a mechanism called apoptotic volume decrease (AVD). As volume-sensitive chloride channels (I (Cl,vol)) are known to play a key role in the regulation of cell volume, this study investigated the role of I (Cl,vol) and AVD in doxorubicin-induced apoptotic cell death in adult rabbit ventricular cardiomyocytes. Exposure of cardiomyocytes to 1 microm doxorubicin induced a rapid and significant reduction in cell volume of cardiomyocytes (average of 15%), i.e. AVD as well as increases in the early markers of apoptosis, annexin V labeling and caspase-3 activity. Doxorubicin also induced the activation of a current characterized as I (Cl,vol) on the basis of the external chloride sensitivity and pharmacological properties with the patch clamp technique. Doxorubicin-induced AVD and apoptosis were both abolished when cardiomyocytes were exposed to the I (Cl,vol) inhibitors 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) (0.1 mM) or indanyloxyacetic acid 94 (IAA-94) (10 microM). The crucial role of I (Cl,vol) during AVD and apoptosis was confirmed using C (2)-ceramide, another pro-apoptotic compound. These results demonstrate that activation of I (Cl,vol) plays a major role in the mechanism leading to cell shrinkage and apoptosis-induced AVD by agents such as doxorubicin or C (2)-ceramide in adult cardiomyocytes. |
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