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Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases

The osmodiuretic agent Mannitol exerts cardioprotection against ischemia and reperfusion (I/R) injury when applied as a pre- and/or postconditioning stimulus. Previously, we demonstrated that these properties are mediated via the activation of mitochondrial ATP-sensitive potassium (mK(ATP)) channels...

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Autores principales: Torregroza, Carolin, Glashoerster, Chiara O., Feige, Katharina, Stroethoff, Martin, Raupach, Annika, Heinen, André, Hollmann, Markus W., Huhn, Ragnar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625521/
https://www.ncbi.nlm.nih.gov/pubmed/34830353
http://dx.doi.org/10.3390/ijms222212471
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author Torregroza, Carolin
Glashoerster, Chiara O.
Feige, Katharina
Stroethoff, Martin
Raupach, Annika
Heinen, André
Hollmann, Markus W.
Huhn, Ragnar
author_facet Torregroza, Carolin
Glashoerster, Chiara O.
Feige, Katharina
Stroethoff, Martin
Raupach, Annika
Heinen, André
Hollmann, Markus W.
Huhn, Ragnar
author_sort Torregroza, Carolin
collection PubMed
description The osmodiuretic agent Mannitol exerts cardioprotection against ischemia and reperfusion (I/R) injury when applied as a pre- and/or postconditioning stimulus. Previously, we demonstrated that these properties are mediated via the activation of mitochondrial ATP-sensitive potassium (mK(ATP)) channels. However, considering Mannitol remains in the extracellular compartment, the question arises as to which receptor and intracellular signaling cascades are involved in myocardial protection by the osmodiuretic substance. Protein kinase B (Akt) and G (PKG), as part of the reperfusion injury salvage kinase (RISK) and/or endothelial nitric oxide (eNOS)/PKG pathway, are two well-investigated intracellular targets conferring myocardial protection upstream of mitochondrial potassium channels. Adenosine receptor subtypes have been shown to trigger different cardioprotective pathways, for example, the reperfusion injury. Further, Mannitol induces an increased activation of the adenosine 1 receptor (A1R) in renal cells conferring its nephroprotective properties. Therefore, we investigated whether (1) Akt and PKG are possible signaling targets involved in Mannitol-induced conditioning upstream of the mK(ATP) channel and/or whether (2) cardioprotection by Mannitol is mediated via activation of the A1R. All experiments were performed on male Wistar rats in vitro employing the Langendorff isolated heart perfusion technique with infarct size determination as the primary endpoint. To unravel possible protein kinase activation, Mannitol was applied in combination with the Akt (MK2206) or PKG (KT5823) inhibitor. In further groups, an A1R blocker (DPCPX) was given with or without Mannitol. Preconditioning with Mannitol (Man) significantly reduced the infarct size compared to the control group. Co-administration of the A1R blocker DPXPC fully abolished myocardial protection of Mannitol. Interestingly and in contrast to the initial hypothesis, neither administration of the Akt nor the PKG blocker had any impact on the cardioprotective properties of Mannitol-induced preconditioning. These results are quite unexpected and show that the protein kinases Akt and PKG—as possible targets of known protective signaling cascades—are not involved in Mannitol-induced preconditioning. However, the cardioprotective effects of Mannitol are mediated via the A1R.
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spelling pubmed-86255212021-11-27 Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases Torregroza, Carolin Glashoerster, Chiara O. Feige, Katharina Stroethoff, Martin Raupach, Annika Heinen, André Hollmann, Markus W. Huhn, Ragnar Int J Mol Sci Article The osmodiuretic agent Mannitol exerts cardioprotection against ischemia and reperfusion (I/R) injury when applied as a pre- and/or postconditioning stimulus. Previously, we demonstrated that these properties are mediated via the activation of mitochondrial ATP-sensitive potassium (mK(ATP)) channels. However, considering Mannitol remains in the extracellular compartment, the question arises as to which receptor and intracellular signaling cascades are involved in myocardial protection by the osmodiuretic substance. Protein kinase B (Akt) and G (PKG), as part of the reperfusion injury salvage kinase (RISK) and/or endothelial nitric oxide (eNOS)/PKG pathway, are two well-investigated intracellular targets conferring myocardial protection upstream of mitochondrial potassium channels. Adenosine receptor subtypes have been shown to trigger different cardioprotective pathways, for example, the reperfusion injury. Further, Mannitol induces an increased activation of the adenosine 1 receptor (A1R) in renal cells conferring its nephroprotective properties. Therefore, we investigated whether (1) Akt and PKG are possible signaling targets involved in Mannitol-induced conditioning upstream of the mK(ATP) channel and/or whether (2) cardioprotection by Mannitol is mediated via activation of the A1R. All experiments were performed on male Wistar rats in vitro employing the Langendorff isolated heart perfusion technique with infarct size determination as the primary endpoint. To unravel possible protein kinase activation, Mannitol was applied in combination with the Akt (MK2206) or PKG (KT5823) inhibitor. In further groups, an A1R blocker (DPCPX) was given with or without Mannitol. Preconditioning with Mannitol (Man) significantly reduced the infarct size compared to the control group. Co-administration of the A1R blocker DPXPC fully abolished myocardial protection of Mannitol. Interestingly and in contrast to the initial hypothesis, neither administration of the Akt nor the PKG blocker had any impact on the cardioprotective properties of Mannitol-induced preconditioning. These results are quite unexpected and show that the protein kinases Akt and PKG—as possible targets of known protective signaling cascades—are not involved in Mannitol-induced preconditioning. However, the cardioprotective effects of Mannitol are mediated via the A1R. MDPI 2021-11-19 /pmc/articles/PMC8625521/ /pubmed/34830353 http://dx.doi.org/10.3390/ijms222212471 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Torregroza, Carolin
Glashoerster, Chiara O.
Feige, Katharina
Stroethoff, Martin
Raupach, Annika
Heinen, André
Hollmann, Markus W.
Huhn, Ragnar
Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases
title Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases
title_full Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases
title_fullStr Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases
title_full_unstemmed Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases
title_short Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases
title_sort mediation of the cardioprotective effects of mannitol discovered, with refutation of common protein kinases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625521/
https://www.ncbi.nlm.nih.gov/pubmed/34830353
http://dx.doi.org/10.3390/ijms222212471
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