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

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World Journal of Cardiology 2022年第4期14卷 220-230页

作者： 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 PharmacyNova Southeastern UniversityFort LauderdaleFL 33328-2018United States

BACKGROUND In the heart,aldosterone(Aldo)binds the mineralocorticoid receptor(MR)to exert damaging,adverse remodeling-promoting *** recently showed that G protein-coupled receptor-kinase(GRK)-5 blocks the cardiac MR by directly phosphorylating it,thereby repressing its transcriptional *** antagonist(MRA)drugs block the cardiac MR reducing morbidity and mortality of advanced human heart ***-steroidal MRAs,such as finerenone,may provide better cardio-protection against Aldo than classic,steroidal MRAs,like spironolactone and *** To investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent *** We used H9c2 cardiomyocytes,which endogenously express the MR and *** GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to *** eplerenone,finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity,thus displaying inverse ***5 is necessary for finerenone’s inverse agonism,since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional *** alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression ***,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 *** 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 ***5 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

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Nicotine-induced adrenal beta-arrestin1 upregulation mediates tobacco-related hyperaldosteronism leading to cardiac dysfunction

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World Journal of Cardiology 2020年第5期12卷 192-202页

作者： natalie cora Jennifer Ghandour Celina Marie Pollard Victoria Lynn Desimine Krysten Elaine Ferraino Janelle Marie Pereyra Rachel Valiente Anastasios Lymperopoulos Laboratory for the Study of Neurohormonal Control of the Circulation Department of Pharmaceutical Sciences(Pharmacology)College of PharmacyNova Southeastern UniversityFort LauderdaleFL 33328-2018United States

BACKGROUND Tobacco-related products,containing the highly addictive nicotine together with numerous other harmful toxicants and carcinogens,have been clearly associated with coronary artery disease,heart failure,stroke,and other heart *** the mechanisms by which nicotine contributes to heart disease is elevation of the renin-angiotensin-aldosterone system(RAAS)***,and its major metabolite in humans cotinine,have been reported to induce RAAS activation,resulting in aldosterone elevation in *** has various direct and indirect adverse cardiac *** is produced by the adrenal cortex in response to angiotensin II(AngII)activating AngII type 1 *** activity increases in chronic smokers,causing raised aldosterone levels(nicotine exposure causes the same in rats).AngII receptors exert their cellular effects via either G proteins or the twoβarrestins(βarrestin1 and-2).AIM Since adrenal?arrestin1 is essential for adrenal aldosterone production and nicotine/cotinine elevate circulating aldosterone levels in humans,we hypothesized that nicotine activates adrenal?arrestin1,which contributes to RAAS activation and heart disease *** We studied human adrenocortical zona glomerulosa H295R cells and found that nicotine and cotinine upregulateβarrestin1 mRNA and protein levels,thereby enhancing AngII-dependent aldosterone synthesis and *** In contrast,siRNA-mediatedβarrestin1 knockdown reversed the effects of nicotine on AngII-induced aldosterone production in H295 R ***,nicotine promotes hyperaldosteronism via adrenalβarrestin1,thereby precipitating cardiac dysfunction,also in vivo,since nicotine-exposed experimental rats with adrenal-specificβarrestin1 knockdown display lower circulating aldosterone levels and better cardiac function than nicotine-exposed control animals with normal adrenalβarrestin1 *** Adrenalβarrestin1 upregulation is one of the mechanisms by whic

关键词： Adrenocortical zona glomerulosa cell Aldosterone βarrestin Nicotine Signal transduction Tobacco-related heart disease

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