ClC-3-independent sensitivity of apoptosis to Cl - channel blockers in mouse cardiomyocytes

Abstract

It has been shown that Cl - /HCO 3- exchangers and Cl - channels, both of which are sensitive to stilbene derivatives, have essential roles in the mechanism of apoptosis induction. Staurosporine-induced apoptosis in neonatal mouse cardiomyocytes was prevented by a stilbene derivative, DIDS. To clarify whether Cl - /HCO 3- exchangers or Cl - channels are targets of DIDS and whether ClC-3 is involved in the apoptotic process, staurosporine-induced reduction of cell viability, DNA laddering and caspase-3 activation were examined in cultured mouse ventricular myocytes derived from wild-type and ClC-3-deficient mice. Staurosporine-induced apoptosis and its DIDS sensitivity in ambient HCO 3- -free conditions in which operation of Cl - /HCO 3- exchangers is minimized were indistinguishable from when HCO 3- was present. Apoptosis was also prevented by application of a non-stilbene-derivative Cl - channel blocker, NPPB, which cannot block Cl - / HCO 3- exchangers. Cardiomyocytes derived from ClC-3-deficient mice similarly underwent apoptosis after exposure to staurosporine; moreover, apoptosis was prevented by application of DIDS or NPPB. Thus, we conclude that in cardiomyocytes, apoptosis is critically dependent on operation not of Cl - /HCO 3- exchangers but of Cl - channels which are distinct from ClC-3. Copyright © 2005 S. Karger AG.