CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
The signaling pathways of CaMKII-dependent induced apoptosis in the ischemic/reperfused hearts involves the Na+/Ca2+ exchanger, the sarcoplasmic reticulum and the mitochondria.
SALAS MA; VALVERDE CA; SAID M; PORTIANSKY EL; MATTIAZZI A
Congreso; Scientific Sessions 2007, American Heart Association; 2007
American Heart Association
Previous results from our laboratory described a signaling pathway triggered by reperfusion that involves activation of Ca2+-calmodulin-dependent protein kinase (CaMKII) and phosphorylation of Thr17 of phospholamban (PLN). This cascade was beneficial for the mechanical and Ca2+i recovery in the reversible ischemia/reperfusion (I/R) injury (stunning) (Valverde et al., 2005). We then described that CaMKII was deleterious in the irreversible I/R injury (Vila-Petroff et al., 2007). To further explore the mechanisms of this effect, Langendorff perfused rat hearts were subjected to global no-flow I/R (45/120 min). Inhibition of CaMKII by 2.5 µM KN-93 (KN), produced a decrease in the infarct size (29.5 ± 6.2 %), in the degree of apoptosis (Fig. 1) and in caspase-3 activity (27.2 ± 6.0 %) with respect to control I/R hearts. Hearts were then submitted to the same I/R protocol in the absence and presence of 5 µM of the following inhibitors: KB-R7943 (KBR), to avoid Ca2+ influx through the Na+/Ca2+ exchanger (NCX), dantrolene (D), to inhibit SR Ca2+ release through the ryanodine receptors and ruthenium red (RR), to inhibit Ca2+ influx to the mitochondria through the Ca2+ uniporter. All these manoeuvres significantly decreased the infarct size and the TUNEL positive cells (apoptosis) with respect to I/R control hearts (Fig. 2). The results indicated a detrimental CaMKII-dependent pathway that leads to apoptosis during the irreversible I/R injury, which may be triggered by Ca2+ influx through the NCX, and involves SR Ca2+ release and mitochondrial Ca2+ uptake. Together with our previous findings, our results reveal a dual effect of CaMKII in the reversible and irreversible I/R injury.