GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone  

作　　者：Celina M Pollard Malka S Suster Natalie Cora Alexandra M Carbone Anastasios Lymperopoulos 

机构地区：[1]Laboratory for the Study of Neurohormonal Control of the Circulation,Department of Pharmaceutical Sciences(Pharmacology),College of Pharmacy,Nova Southeastern University,Fort Lauderdale,FL 33328-2018,United States

出　　处：《World Journal of Cardiology》2022年第4期220-230,共11页世界心脏病学杂志（英文版）（电子版）

摘　　要：BACKGROUND In the heart,aldosterone(Aldo)binds the mineralocorticoid receptor(MR)to exert damaging,adverse remodeling-promoting effects.We recently showed that G protein-coupled receptor-kinase(GRK)-5 blocks the cardiac MR by directly phosphorylating it,thereby repressing its transcriptional activity.MR antagonist(MRA)drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure.Non-steroidal MRAs,such as finerenone,may provide better cardio-protection against Aldo than classic,steroidal MRAs,like spironolactone and eplerenone.AIM To investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade.METHODS We used H9c2 cardiomyocytes,which endogenously express the MR and GRK5.RESULTS GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone.Unlike eplerenone,finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity,thus displaying inverse agonism.GRK5 is necessary for finerenone’s inverse agonism,since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity.Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels.Finally,GRK5 is necessary for the antiapoptotic,anti-oxidative,and anti-fibrotic effects of both finerenone and eplerenone against Aldo,as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis,oxidative stress,and fibrosis.CONCLUSION Finerenone,but not eplerenone,induces GRK5-dependent cardiac MR inhibition,which underlies,at least in part,its higher potency and efficacy,compared to eplerenone,as an MRA in the heart.GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.

关 键 词：ALDOSTERONE Cardiac myocyte Finerenone G protein-coupled receptor kinase-5 Mineralocorticoid receptor antagonist Signal transduction 

分 类 号：R54[医药卫生—心血管疾病]