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Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion

BACKGROUND: Identification of signaling pathways altered at early stages after cardiac ischemia/reperfusion (I/R) is crucial to develop timely therapies aimed at reducing I/R injury. The expression of G protein-coupled receptor kinase 2 (GRK2), a key signaling hub, is up-regulated in the long-term i...

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Autores principales: Penela, Petronila, Inserte, Javier, Ramos, Paula, Rodriguez-Sinovas, Antonio, Garcia-Dorado, David, Mayor, Federico
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838402/
https://www.ncbi.nlm.nih.gov/pubmed/31594751
http://dx.doi.org/10.1016/j.ebiom.2019.09.019
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author Penela, Petronila
Inserte, Javier
Ramos, Paula
Rodriguez-Sinovas, Antonio
Garcia-Dorado, David
Mayor, Federico
author_facet Penela, Petronila
Inserte, Javier
Ramos, Paula
Rodriguez-Sinovas, Antonio
Garcia-Dorado, David
Mayor, Federico
author_sort Penela, Petronila
collection PubMed
description BACKGROUND: Identification of signaling pathways altered at early stages after cardiac ischemia/reperfusion (I/R) is crucial to develop timely therapies aimed at reducing I/R injury. The expression of G protein-coupled receptor kinase 2 (GRK2), a key signaling hub, is up-regulated in the long-term in patients and in experimental models of heart failure. However, whether GRK2 levels change at early time points following myocardial I/R and its functional impact during this period remain to be established. METHODS: We have investigated the temporal changes of GRK2 expression and their potential relationships with the cardioprotective AKT pathway in isolated rat hearts and porcine preclinical models of I/R. FINDINGS: Contrary to the maladaptive up-regulation of GRK2 reported at later times after myocardial infarction, successive GRK2 phosphorylation at specific sites during ischemia and early reperfusion elicits GRK2 degradation by the proteasome and calpains, respectively, thus keeping GRK2 levels low during early I/R in rat hearts. Concurrently, I/R promotes decay of the prolyl-isomerase Pin1, a positive regulator of AKT stability, and a marked loss of total AKT protein, resulting in an overall decreased activity of this pro-survival pathway. A similar pattern of concomitant down-modulation of GRK2/AKT/Pin1 protein levels in early I/R was observed in pig hearts. Calpain and proteasome inhibition prevents GRK2/Pin1/AKT degradation, restores bulk AKT pathway activity and attenuates myocardial I/R injury in isolated rat hearts. INTERPRETATION: Preventing transient degradation of GRK2 and AKT during early I/R might improve the potential of endogenous cardioprotection mechanisms and of conditioning strategies.
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spelling pubmed-68384022019-11-12 Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion Penela, Petronila Inserte, Javier Ramos, Paula Rodriguez-Sinovas, Antonio Garcia-Dorado, David Mayor, Federico EBioMedicine Research paper BACKGROUND: Identification of signaling pathways altered at early stages after cardiac ischemia/reperfusion (I/R) is crucial to develop timely therapies aimed at reducing I/R injury. The expression of G protein-coupled receptor kinase 2 (GRK2), a key signaling hub, is up-regulated in the long-term in patients and in experimental models of heart failure. However, whether GRK2 levels change at early time points following myocardial I/R and its functional impact during this period remain to be established. METHODS: We have investigated the temporal changes of GRK2 expression and their potential relationships with the cardioprotective AKT pathway in isolated rat hearts and porcine preclinical models of I/R. FINDINGS: Contrary to the maladaptive up-regulation of GRK2 reported at later times after myocardial infarction, successive GRK2 phosphorylation at specific sites during ischemia and early reperfusion elicits GRK2 degradation by the proteasome and calpains, respectively, thus keeping GRK2 levels low during early I/R in rat hearts. Concurrently, I/R promotes decay of the prolyl-isomerase Pin1, a positive regulator of AKT stability, and a marked loss of total AKT protein, resulting in an overall decreased activity of this pro-survival pathway. A similar pattern of concomitant down-modulation of GRK2/AKT/Pin1 protein levels in early I/R was observed in pig hearts. Calpain and proteasome inhibition prevents GRK2/Pin1/AKT degradation, restores bulk AKT pathway activity and attenuates myocardial I/R injury in isolated rat hearts. INTERPRETATION: Preventing transient degradation of GRK2 and AKT during early I/R might improve the potential of endogenous cardioprotection mechanisms and of conditioning strategies. Elsevier 2019-10-05 /pmc/articles/PMC6838402/ /pubmed/31594751 http://dx.doi.org/10.1016/j.ebiom.2019.09.019 Text en © 2019 The Authors. Published by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Penela, Petronila
Inserte, Javier
Ramos, Paula
Rodriguez-Sinovas, Antonio
Garcia-Dorado, David
Mayor, Federico
Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion
title Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion
title_full Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion
title_fullStr Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion
title_full_unstemmed Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion
title_short Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion
title_sort degradation of grk2 and akt is an early and detrimental event in myocardial ischemia/reperfusion
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838402/
https://www.ncbi.nlm.nih.gov/pubmed/31594751
http://dx.doi.org/10.1016/j.ebiom.2019.09.019
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