Pollard CM, Suster MS, Cora N, Carbone AM, Lymperopoulos A. GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone. World J Cardiol 2022; 14(4): 220-230 [PMID: 35582468 DOI: 10.4330/wjc.v14.i4.220]
Corresponding Author of This Article
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
Research Domain of This Article
Cardiac & Cardiovascular Systems
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
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
ARTICLE HIGHLIGHTS
Research background
Different mineralocorticoid receptor (MR) antagonists (MRAs) have different potencies at the cardiac MR blockade. G protein-coupled receptor kinase (GRK)-5 phosphorylates the MR in the heart and inhibits its transcriptional activity.
Research motivation
The authors wanted to compare two different MRAs, eplerenone and finerenone, in their ability to stimulate GRK5-dependent MR inhibition in cardiac myocytes.
Research objectives
The authors sought to identify a mechanism for the increased effectiveness of finerenone over eplerenone at blocking cardiac MR.
Research methods
The authors studied MR phosphorylation and activity in cardiomyocytes in response to eplerenone or finerenone treatments.
Research results
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.
Research conclusions
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.
Research perspectives
GRK5 is an essential mediator of finerenone’s effects on cardiac aldosterone antagonism.
