Sodium Homeostasis and Cardiac Function.

MARTIN G. VILA PETROFF

Kyoto

Congreso; XX World Congress of the International Society for Heart Research (ISHR); 2010

International Society for Heart Research

SODIUM OVERLOAD-TRIGGERED APOPTOSIS IN THE FAILING HEART.Martin Vila Petroff. Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina. Alterations in intracellular Ca2+ handling and apoptosis have been shown to underlie the contractile dysfunction of the failing heart (FH). Na+i is elevated in the FH and thus may influence Ca2+ homeostasis thorough its effect on Na+/Ca2+ exchanger (NCX) activity. Alterations in Ca2+ handling have also been proposed as the initial trigger for apoptosis. However, the impact of elevated Na+i on apoptosis has not yet been evaluated. In this study we assessed the role of elevated Na+i on apoptosis and examined the subcellular mechanisms involved. For this purpose, we used the Na+/K+ ATPase inhibitor ouabain (oua), to increase [Na+]i to mimic the levels observed in the FH and examine the effect of this increase on cell viability and apoptosis. 24 hs culture in the presence of oua significantly reduced myocyte viability and increased apoptosis (enhanced caspase-3 activity and increased Bax/Bcl-2). Using specific pharmacological tools and genetic manipulation we determined that elevated Na+i triggers an apoptotic cascade that involves the NCX and CaMKII as a downstream effector. Our findings also indicate that CaMKII inhibition can prevent oua-induced apoptosis without affecting glycoside inotropy suggesting the potential use of CaMKII inhibitors as an adjunct to digitalis treatment for cardiovascular disease.