CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
. Increased susceptibility of cardiomyocytes of male hearts to ischemia/reperfusion injury: role of Ca2+ and CaMKII.
VILA PETROFF, MARTÍN G; CURL, CLAIRE; BELL, JAMES; MATTIAZZI, ALICIA; LEA DELBRIDGE
New London, USA
Congreso; Gordon Conference 2008; 2008
Important cardiac-specific sex differences have been previously reported. Among these, we have previously shown that males are more susceptible to ischemia/reperfusion (I/R) injury than females. Ca2+ overload during early reperfusion has been shown to play a critical role in cardiac I/R injury and recent evidence has highlighted CaMKII activation as the promoter of cellular apoptosis and necrosis during I/R injury. However, whether sex related differences in Ca2+ handling and/or CaMKII activation underlie the distinct vulnerability to ischemic damage has not been investigated. In this study we used a model of 20 min simulated I/R in myocytes isolated from hearts of adult male and female Sprague Dawley rats, loaded with fura-2 to examine whether the enhanced susceptibility to I/R injury of males could be attributed to alterations in Ca2+ dynamics and/or differences in CaMKII activity. For this purpose, experiments where performed in the absence and presence of the CaMKII inhibitor, KN-93, and cell shortening and viability were monitored simultaneously. Although male myocytes showed significantly greater Ca2+ transients at base line, contractile recovery and Ca2+ handling during the I/R protocol was not different between the surviving cells from both groups. However, cell mortality during reperfusion was exacerbated in male cells (11 out of 16 cells died during reperfusion) compared to females (1 out of 10 cells died during reperfusion). CaMKII inhibition attenuated diastolic contracture during reperfusion of both male and female myocytes but did not significantly improve contractile recovery. In contrast, CaMKII inhibition, markedly improved cell viability after reperfusion. These results suggest that male susceptibility to I/R injury is determined by a reduced tolerance of male cells to I/R-induced necrosis and not to depressed contractile recovery of the surviving cells. The results further suggest that enhanced CaMKII activity possibly due to larger steady state Ca2+ transients in males could be responsible for cardiac specific sex differences.