Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Cardiol. Apr 26, 2022; 14(4): 220-230
Published online Apr 26, 2022. doi: 10.4330/wjc.v14.i4.220
GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone
Celina M Pollard, Malka S Suster, Natalie Cora, Alexandra M Carbone, Anastasios Lymperopoulos
Celina M Pollard, Malka S Suster, Natalie Cora, Alexandra M Carbone, Anastasios Lymperopoulos, 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
Author contributions: Pollard CM, Suster MS, Cora N, and Carbone AM performed all experiments and assisted with data analysis; Lymperopoulos A supervised the project, performed data analysis, provided funding for the study, and wrote the manuscript; and All authors have read and approved the manuscript.
Institutional review board statement: All methods were carried out in accordance with the relevant guidelines and regulations.
Conflict-of-interest statement: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Data sharing statement: This Declaration acknowledges that this paper adheres to the principles for transparent reporting and scientific rigor of preclinical research recommended by funding agencies, publishers and other organizations engaged with supporting research. All data presented and associated source files are available upon request.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Anastasios Lymperopoulos, BPharm, MSc, PhD, FAHA, FESC, Associate Professor, Director, Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, 3200 S. University Dr., HPD (Terry) Bldg/Room 1338, Fort Lauderdale, FL 33328-2018, United States. al806@nova.edu
Received: December 10, 2021
Peer-review started: December 10, 2021
First decision: February 15, 2022
Revised: February 17, 2022
Accepted: March 27, 2022
Article in press: March 27, 2022
Published online: April 26, 2022
Processing time: 129 Days and 4 Hours
Abstract
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 anti-apoptotic, 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

Keywords: Aldosterone; Cardiac myocyte; Finerenone; G protein-coupled receptor kinase-5; Mineralocorticoid receptor antagonist; Signal transduction

Core Tip: G protein-coupled receptor-kinase (GRK)-5 blocks the cardiac actions of aldosterone via phosphorylation of the mineralocorticoid receptor (MR). We show here that the non-steroidal MR antagonist (MRA) finerenone may provide better cardio-protection against aldosterone than classic, steroidal MRAs, like eplerenone, thanks to induction of GRK5’s phosphorylation and subsequent blockade of cardiac MR. GRK5 is necessary for the anti-apoptotic, anti-oxidative, and anti-fibrotic effects of both finerenone and eplerenone against aldosterone but also for the higher efficacy/potency of the former drug at producing all these effects in cardiomyocytes. Thus, GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.