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

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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Main Authors: Petronila Penela, Javier Inserte, Paula Ramos, Antonio Rodriguez-Sinovas, David Garcia-Dorado, Federico Mayor, Jr
Format: Article
Language:English
Published: Elsevier 2019-10-01
Series:EBioMedicine
Online Access:http://www.sciencedirect.com/science/article/pii/S2352396419306231
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spelling doaj-857a76c86336481095934286f38a09462020-11-25T01:06:05ZengElsevierEBioMedicine2352-39642019-10-0148605618Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusionResearch in contextPetronila Penela0Javier Inserte1Paula Ramos2Antonio Rodriguez-Sinovas3David Garcia-Dorado4Federico Mayor, Jr5Departamento de Biología Molecular, Centro de Biología Molecular “Severo Ochoa” (UAM-CSIC), 28049 Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, SpainCIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; Cardiovascular Diseases Research Group, Vall d'Hebron University Hospital and Research Institute, 08035 Barcelona, Spain; Universitat Autònoma de Barcelona, 08193 Barcelona, SpainDepartamento de Biología Molecular, Centro de Biología Molecular “Severo Ochoa” (UAM-CSIC), 28049 Madrid, SpainCIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; Cardiovascular Diseases Research Group, Vall d'Hebron University Hospital and Research Institute, 08035 Barcelona, Spain; Universitat Autònoma de Barcelona, 08193 Barcelona, SpainCIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; Cardiovascular Diseases Research Group, Vall d'Hebron University Hospital and Research Institute, 08035 Barcelona, Spain; Universitat Autònoma de Barcelona, 08193 Barcelona, SpainDepartamento de Biología Molecular, Centro de Biología Molecular “Severo Ochoa” (UAM-CSIC), 28049 Madrid, Spain; Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain; Corresponding author at: Centro de Biologia Molecular “Severo Ochoa”, c/Nicolás Cabrera 1, Universidad Autónoma de Madrid, 28049 Madrid, Spain.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. Keywords: GRK2, AKT, Ischemia-reperfusion, Cardioprotection, Pin1, Proteasome, Calpainshttp://www.sciencedirect.com/science/article/pii/S2352396419306231
collection DOAJ
language English
format Article
sources DOAJ
author Petronila Penela
Javier Inserte
Paula Ramos
Antonio Rodriguez-Sinovas
David Garcia-Dorado
Federico Mayor, Jr
spellingShingle Petronila Penela
Javier Inserte
Paula Ramos
Antonio Rodriguez-Sinovas
David Garcia-Dorado
Federico Mayor, Jr
Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusionResearch in context
EBioMedicine
author_facet Petronila Penela
Javier Inserte
Paula Ramos
Antonio Rodriguez-Sinovas
David Garcia-Dorado
Federico Mayor, Jr
author_sort Petronila Penela
title Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusionResearch in context
title_short Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusionResearch in context
title_full Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusionResearch in context
title_fullStr Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusionResearch in context
title_full_unstemmed Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusionResearch in context
title_sort degradation of grk2 and akt is an early and detrimental event in myocardial ischemia/reperfusionresearch in context
publisher Elsevier
series EBioMedicine
issn 2352-3964
publishDate 2019-10-01
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. Keywords: GRK2, AKT, Ischemia-reperfusion, Cardioprotection, Pin1, Proteasome, Calpains
url http://www.sciencedirect.com/science/article/pii/S2352396419306231
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