Degradation of GRK2 and AKT is an early and detrimental event in myocardial ischemia/reperfusion
Penela, Petronila (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Inserte, Javier (Universitat Autònoma de Barcelona)
Ramos, Paula (Centro de Biología Molecular Severo Ochoa)
Rodriguez-Sinovas, Antonio (Universitat Autònoma de Barcelona)
García-Dorado, David (Universitat Autònoma de Barcelona)
Mayor, F. (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)

Data:	2019
Resum:	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.
Ajuts:	Instituto de Salud Carlos III CB16/11-00479 Instituto de Salud Carlos III CB16/11-00278 Ministerio de Economía y Competitividad SAF2017-84125-R Instituto de Salud Carlos III RETICS-RIC-RD12-0042-0021 Instituto de Salud Carlos III PI-16-00232
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	GRK2 ; AKT ; Ischemia-reperfusion ; Cardioprotection ; Pin1 ; Proteasome ; Calpains ; GPCR, G-protein coupled receptor ; GRK2, G-protein coupled receptor kinase 2 ; HF, heart failure ; I/R, Ischemia/Reperfusion ; MI, myocardial infarction ; RISK, reperfusion injury salvage kinase pathway
Publicat a:	EBioMedicine, Vol. 48 (october 2019) , p. 605-618, ISSN 2352-3964

DOI: 10.1016/j.ebiom.2019.09.019
PMID: 31594751

14 p, 2.3 MB

El registre apareix a les col·leccions:
Articles > Articles de recerca
Articles > Articles publicats