CONICET | Buscador de Institutos y Recursos Humanos

Hearts subjected to prolonged I/R periods present a major loss of cardiac myocytes due to necrotic and apoptotic death. We previously showed that CaMKII activation has a detrimental role during the myocyte death process. (Vila-Petroff M et al, Cardiovasc Res., 2007). Our aim was to gain further insight in the signaling pathway involved in this effect. Paced rat hearts (n=5) were subjected to global I/R (45/120min). The results showed that CaMKII is activated at the beginning of R, as indicated by the phosphorylation of its typical substrate, the Thr17 site of phospholamban. This phosphorylation diminished by inhibiting the Ca2+ influx through the reverse mode of the Na+/ Ca2+ exchanger but not by blocking L-type Ca2+ channels. Moreover, transgenic mice (n= 7) with selective inhibition of the CaMKII at the SR level (SR-AIP) subjected to the same protocol of I/R, showed a significant decrease of the infarct size with respect to wild type animals (WT): SR-AIP: 8.78±1.8%, WT: 24.21±3.2%, LDH release: SR-AIP: 36.9 ± 15.3 U/l, WT 114.14±20.46 U/l and the number of apoptotic nuclei: SR-AIP: 2.4±0.8%, WT: 14.4±1.29%. Our results point to the SR as playing a major role in the CaMKII-dependent signaling pathway leading to irreversible ischemia/ reperfusion injury