Timed use of digoxin prevents heart ischemia-reperfusion injury through a REV-ERBα-UPS signaling pathway.
Fiche publication
Date publication
novembre 2022
Journal
Nature cardiovascular research
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah
Tous les auteurs :
Vinod M, Berthier A, Maréchal X, Gheeraert C, Boutry R, Delhaye S, Annicotte JS, Duez H, Hovasse A, Cianférani S, Montaigne D, Eeckhoute J, Staels B, Lefebvre P
Lien Pubmed
Résumé
Myocardial ischemia-reperfusion injury (MIRI) induces life-threatening damages to the cardiac tissue and pharmacological means to achieve cardioprotection are sorely needed. MIRI severity varies along the day-night cycle and is molecularly linked to components of the cellular clock including the nuclear receptor REV-ERBα, a transcriptional repressor. Here we show that digoxin administration in mice is cardioprotective when timed to trigger REV-ERBα protein degradation. In cardiomyocytes, digoxin increases REV-ERBα ubiquitinylation and proteasomal degradation, which depend on REV-ERBα ability to bind its natural ligand, heme. Inhibition of the membrane-bound Src tyrosine-kinase partially alleviated digoxin-induced REV-ERBα degradation. In untreated cardiomyocytes, REV-ERBα proteolysis is controlled by known (HUWE1, FBXW7, SIAH2) or novel (CBL, UBE4B) E3 ubiquitin ligases and the proteasome subunit PSMB5. Only SIAH2 and PSMB5 contributed to digoxin-induced degradation of REV-ERBα. Thus, controlling REV-ERBα proteostasis through the ubiquitin-proteasome system is an appealing cardioprotective strategy. Our data support the timed use of clinically-approved cardiotonic steroids in prophylactic cardioprotection.
Référence
Nat Cardiovasc Res. 2022 11 3;1(11):990-1005