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<sub>ATP&...

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Autores principales:	Carolin Torregroza, Chiara O. Glashoerster, Katharina Feige, Martin Stroethoff, Annika Raupach, André Heinen, Markus W. Hollmann, Ragnar Huhn
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	mannitol myocardial infarction preconditioning adenosine receptor protein kinase B protein kinase G Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/08b32e1ec5c3408488f756551c150086
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spelling	oai:doaj.org-article:08b32e1ec5c3408488f756551c1500862021-11-25T17:56:57ZMediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases10.3390/ijms2222124711422-00671661-6596https://doaj.org/article/08b32e1ec5c3408488f756551c1500862021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12471https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The 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<sub>ATP</sub>) 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<sub>ATP</sub> 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.Carolin TorregrozaChiara O. GlashoersterKatharina FeigeMartin StroethoffAnnika RaupachAndré HeinenMarkus W. HollmannRagnar HuhnMDPI AGarticlemannitolmyocardial infarctionpreconditioningadenosine receptorprotein kinase Bprotein kinase GBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12471, p 12471 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	mannitol myocardial infarction preconditioning adenosine receptor protein kinase B protein kinase G Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	mannitol myocardial infarction preconditioning adenosine receptor protein kinase B protein kinase G Biology (General) QH301-705.5 Chemistry QD1-999 Carolin Torregroza Chiara O. Glashoerster Katharina Feige Martin Stroethoff Annika Raupach André Heinen Markus W. Hollmann Ragnar Huhn Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases
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<sub>ATP</sub>) 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<sub>ATP</sub> 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.
format	article
author	Carolin Torregroza Chiara O. Glashoerster Katharina Feige Martin Stroethoff Annika Raupach André Heinen Markus W. Hollmann Ragnar Huhn
author_facet	Carolin Torregroza Chiara O. Glashoerster Katharina Feige Martin Stroethoff Annika Raupach André Heinen Markus W. Hollmann Ragnar Huhn
author_sort	Carolin Torregroza
title	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_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_sort	mediation of the cardioprotective effects of mannitol discovered, with refutation of common protein kinases
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/08b32e1ec5c3408488f756551c150086
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Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases

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