Desmin aggrephagy in rat and human ischemic heart failure through PKCζ and GSK3β as upstream signaling pathways

Autor: Bouvet, Marion, Dubois-Deruy, Emilie, Turkieh, Annie, Mulder, Paul, Peugnet, Victoriane, Chwastyniak, Maggy, Beseme, Olivia, Dechaumes, Arthur, Amouyel, Philippe, Richard, Vincent, Lamblin, Nicolas, Pinet, Florence
Přispěvatelé: Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by grants from the E.U. FP7 HOMAGE (305507), F-CRIN INI-CRT, and the 'Agence Nationale de la Recherche' ANR blanc-SVSE1 (ANR-10-BLAN-1104). MB was supported by grants from 'Groupe de Reflexion sur la Recherche Cardiovasculaire', EDD was supported by grants from 'Region Hauts de France', 'Institut Pasteur de Lille' and 'Fondation Lefoulon Delalande'. AT was supported by grants from 'ERA-CVD through 'Agence Nationale de la Recherche' and 'Féderation Française de Cardiologie'. FP has received a grant by the French Government, managed by the National Research Agency (ANR) under the program 'Investissements d’avenir' with the reference ANR-16-RHUS-0003. EDD, AT, PM, VR, NL, and FP are members of FHU-CARNAVAL., ANR-10-BLAN-1104,PHOGIHF,Balance phosphorylation / O-GlcNAc dans l'insuffisance cardiaque: Rôles physiopathologiques et intérêt en tant que biomarqueurs(2010), ANR-16-RHUS-0003,STOP-AS,STOP-AS(2016), European Project: 305507,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,HOMAGE(2013)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Cell Death Discovery
Cell Death Discovery, Springer Nature, 2021, 7 (1), pp.153. ⟨10.1038/s41420-021-00549-2⟩
Cell Death Discovery, Vol 7, Iss 1, Pp 1-13 (2021)
Cell Death Discovery, 2021, 7 (1), pp.153. ⟨10.1038/s41420-021-00549-2⟩
ISSN: 2058-7716
Popis: International audience; Post-translational modifications of cardiac proteins could participate to left contractile dysfunction resulting in heart failure. Using a rat model of ischemic heart failure, we showed an accumulation of phosphorylated desmin leading to toxic aggregates in cardiomyocytes, but the cellular mechanisms are unknown. The same rat model was used to decipher the kinases involved in desmin phosphorylation and the proteolytic systems present in rat and human failing hearts. We used primary cultures of neonate rat cardiomyocytes for testing specific inhibitors of kinases and for characterizing the autophagic processes able to clear desmin aggregates. We found a significant increase of active PKCζ, no modulation of ubitiquitin-proteasome system, a defect in macroautophagy, and an activation of chaperone-mediated autophagy in heart failure rats. We validated in vitro that PKCζ inhibition induced a significant decrease of GSK3β and of soluble desmin. In vitro activation of ubiquitination of proteins and of chaperone-mediated autophagy is able to decrease soluble and insoluble forms of desmin in cardiomyocytes. These data demonstrate a novel signaling pathway implicating activation of PKCζ in desmin phosphorylation associated with a defect of proteolytic systems in ischemic heart failure, leading to desmin aggrephagy. Our in vitro data demonstrated that ubiquitination of proteins and chaperone-mediated autophagy are required for eliminating desmin aggregates with the contribution of its chaperone protein, α-crystallin Β-chain. Modulation of the kinases involved under pathological conditions may help preserving desmin intermediate filaments structure and thus protect the structural integrity of contractile apparatus of cardiomyocytes by limiting desmin aggregates formation.
Databáze: OpenAIRE
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