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Mitigation of postischemic cardiac contractile dysfunction by CaMKII inhibition: effects on programmed necrotic and apoptotic cell death

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Abstract

While Ca2+/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/dm3) 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.

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Acknowledgments

Authors would like to thank Mrs. V. Hassova for her indispensable help. This study was supported by Grants UK/430/2013, VEGA 1/0638/12, VEGA 2/0054/11, APVV 0102-11, and APVV 0523-10.

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Odbojarov 10, 83232, Bratislava, Slovak Republic

    Adrian Szobi, Tomas Rajtik & Adriana Adameova

  2. Institute for Heart Research, Slovak Academy of Sciences, Dubravska cesta 9, 84005, Bratislava, Slovak Republic

    Slavka Carnicka & Tana Ravingerova

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  1. Adrian Szobi
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  2. Tomas Rajtik
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  3. Slavka Carnicka
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  4. Tana Ravingerova
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  5. Adriana Adameova
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Correspondence to Adriana Adameova.

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Szobi, A., Rajtik, T., Carnicka, S. et al. Mitigation of postischemic cardiac contractile dysfunction by CaMKII inhibition: effects on programmed necrotic and apoptotic cell death. Mol Cell Biochem 388, 269–276 (2014). https://doi.org/10.1007/s11010-013-1918-x

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  • DOI: https://doi.org/10.1007/s11010-013-1918-x

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