CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Dual role of CaMKII in ischemia/reperfusion injury
Autor/es:
CECILIA MUNDIÑA-WEILENMANN; VILA PETROFF, MARTÍN G; SALAS, MARGARITA A; SAID M; CARLOS VALVERDE; PORTIANSKY ENRIQUE; LETICIA VITTONE; KRANIAS EVANGELIA; MARTTIAZZI
Lugar:
New London - Estado de New Hampshire, USA
Reunión:
Congreso; Gordon Conference 2006; 2006
Institución organizadora:
Gordon Research Conference
Resumen:
Dual role of CaMKII in ischemia/reperfusion injury C.Mundiña-Weilenmann*, M Vila-Petroff*, M Salas, M Said, C Valverde,  E. Portiansky, L. Vittone, E. Kranias and  A. Mattiazzi Experimental evidence indicates that the early phase of reperfusion is of particular relevance for reducing the damage of the ischemic heart, since cardiac injury may occur during this phase, in addition to the insult produced by the preceding ischemia. Previous results from our own laboratory were the first to describe a cascade of events triggered by reperfusion that involves Na+/H+ and Na+/Ca2+ exchangers activation, enhanced calcium influx, activation of calcium-calmodulin-dependent protein kinase (CaMKII) and phosphorylation of Thr17 of phospholamban (PLB). PLB is the sarcoplasmic reticulum (SR) protein that in the dephosphorylated state tonically inhibits the SR calcium pump (SERCA2a). Phosphorylation of Thr17 site of PLB at the beginning of reperfusion precedes and is necessary for the recovery of relaxation, contractility and intracellular calcium handling in the reversible ischemia/reperfusion (I/R) injury, also known as stunned heart. However, the role of CaMKII-dependent phosphorylations in the irreversible I/R injury is not known. To address this issue, the present experiments were performed in the isovolumic Langendorff perfused rat hearts subjected to global no-flow I/R (45 min/120 min) and in isolated myocytes submitted to a protocol of simulated I/R (60 min normoxia/ 40 min anoxia/ 60 min reoxygenation), either in the absence (Control) or presence of CaMKII-inhibition [KN-93 (KN) or the more specific inhibitor AIP]. In the control hearts, phosphorylation of PLB followed a similar pattern as that described in the stunned heart: there was a significant increase in the phosphorylation of Thr17 of PLB at the beginning of reperfusion that then decayed towards pre-ischemic values. This phosphorylation pattern indicated an increase in CaMKII activity at the beginning of reperfusion and was blunted by 1-5 µM KN-93. In the presence of KN-93, hearts exhibited slight but significantly improved recovery of contractile performance at the end of the 120 min reperfusion period, when compared with Controls. This recovery was associated with significant decreases in the extent of infarction, lactate dehydrogenase release (LDH), TUNEL positive (apoptotic) cells (Figure) and caspase-3 activity, when compared with control hearts.  In the isolated myocytes, 1 µM of either KN-93 or AIP completely prevented I/R cell mortality, whereas overexpression of CaMKII decreased cellular viability from 52 ± 3 % (βgal) to 26 ± 2 %. The present findings, taken together with our previous results, indicate that CaMKII-activation at the beginning of reperfusion is beneficial for the recovery of contractility during stunning but detrimental in the irreversible I/R injury. * Both authors contributed equally to this work.
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