title: Mitigation of postischemic cardiac contractile dysfunction by CaMKII inhibition: effects on programmed necrotic and apoptotic cell death.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Odbojarov 10, 83232, Bratislava, Slovak Republic.
authors.forename: Adrian
authors.initials: A
authors.lastname: Szobi
authors.forename: Tomas
authors.initials: T
authors.lastname: Rajtik
authors.forename: Slavka
authors.initials: S
authors.lastname: Carnicka
authors.forename: Tana
authors.initials: T
authors.lastname: Ravingerova
authors.forename: Adriana
authors.initials: A
authors.lastname: Adameova
mesh_terms: D000818:Animals; D017209:Apoptosis; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors*; D053148:Caspase 3 / Q000096:biosynthesis; D053181:Caspase 8 / Q000096:biosynthesis; D053453:Caspase 9 / Q000096:biosynthesis; D045304:Cytochromes c / Q000096:biosynthesis; D006352:Heart Ventricles / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D009336:Necrosis / Q000473:pathology*; D028861:Nuclear Pore Complex Proteins / Q000096:biosynthesis; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D045304:Cytochromes c; D028861:Nuclear Pore Complex Proteins; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; C119724:AGFG1 protein, human; C072105:KN 93; D000096926:Benzenesulfonamides; C499320:PARP1 protein, human