While
Ca(2+)/calmodulin-dependent protein kinase II (
CaMKII) has been suggested to be an important
protein regulating heart function upon
ischemia/reperfusion (I/R), the mechanisms responsible are not fully known. Furthermore, it is not known whether
CaMKII activation can modulate necroptosis, a recently described form of programmed cell death. In order to investigate these issues, Langendroff-perfused rat hearts were subjected to global
ischemia and reperfusion, and
CaMKII inhibition was achieved by adding the
CaMKII inhibitor
KN-93 (0.5 μmol/dm(3)) to the perfusion
solution before the induction of
ischemia. Immunoblotting was used to detect changes in expression of
proteins modulating both necroptotic and apoptotic cell death.
CaMKII inhibition normalized I/R induced increases in expression of necroptotic RIP1 and
caspase-8 along with
proteins of the intrinsic apoptotic pathway, namely
cytochrome c and
caspase-9. In addition, it increased the Bcl-2/Bax ratio and reduced
caspase-3 and cleaved PARP1 content suggesting reduction of cell death. These changes coexisted with improvement of postischemic contractile function. On the other hand, there was no correlation between levels of pT287-CaMKIIδ and LVDP recovery after I/R. These results demonstrate for the first time that
CaMKII inhibition may mitigate cardiac contractile dysfunction, at least partially, by limiting the contents of not only apoptotic, but also necroptotic
proteins. Phosphorylation of
CaMKII seems unlikely to determine the degree of postischemic recovery of contractile function.