CIC   05421
Unidad Ejecutora - UE
congresos y reuniones científicas
Partial Inhibition of Na+/K+-ATPase by Ouabain Induces Apoptosis in Adult Rat Cardiac Myocytes
New London, NH, USA
Congreso; Gordon Conference 2008; 2008
Institución organizadora:
Gordon Conference 2008
Partial Inhibition of Na+/K+-ATPase by Ouabain Induces Apoptosis in Adult Rat Cardiac Myocytes. Luciana Sapia, Alicia Mattiazzi and Martin Vila Petroff.   The positive inotropic effect produced by partial inhibition of Na+/K+ ATPase with digitalis has been used for the treatment of heart failure for over 200 years. Recently, acute administration of toxic doses of oubain has been shown to induce cardiac myocyte apoptosis. However, whether prolonged administration of non toxic doses of ouabain can also promote cardiac myocyte cell death has never been explored. In addition to the well established increase in Ca2+i via the reverse mode of the Na+/Ca2+ exchanger (NCX), ouabain has been shown to activate several signaling pathways with opposing effect on cardiac myocyte survival (ERK1/2; PI3K/AKT). The aim of this study was to assess whether non toxic doses of ouabain can induce cardiac myocytes apoptosis and if so, to examine the underlying mechanisms involved.  For this purpose, isolated rat cardiac myocytes which have been shown to have reduced digitalis sensitivity were cultured for 24 hrs in the presence or absence of 2 µM ouabain. Cell viabilityapoptosis assays showed that oubain produced a 43 ± 5% decrease in cell viability at least in part due to apoptosis as assessed by enhanced caspase-3 activity and decreased Bcl-2/Bax ratio. Ouabain-induced reduction in cell viability was completely prevented by the NCX inhibitor KB-R7943 and rescued by the CamKII inhibitor, KN93. CamKII inhibition did not affect the oubain-induced positive inotropic effect. However, whereas ERK1/2 inhibition with PD-98059 did not affect ouabain-induced cell death, PI3K/AKT pathway inhibition with wortmannin, exacerbated the deleterious effect of ouabain on cardiac myocyte viability.  We conclude that the increase in Ca2+ responsible for the positive inotropic effect of ouabain also promotes the activation of an apoptotic cascade that involves CamKII as the down stream effector. Ouabain simultaneously activates an antiapoptotic cascade involving AKT which is however, insufficient to completely repress apoptosis. The finding that KN93 prevents oubain-induced apoptosis without affecting its positive inotropic effect suggests the potential use of CamKII inhibitors as an adjunct to digitalis treatment. * P<0.05 vs. control; # P<0.05 vs. ouabain