Current and future G protein-coupled receptor signaling targets for heart failure therapy

Siryk-Bathgate, Ashley; Dabul, Samalia; Lymperopoulos, Anastasios

doi:10.2147/dddt.s35905

Cited by 20 publications

(6 citation statements)

References 105 publications

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“…Finally, there is also the obvious mechanistic question of how exactly finerenone, not known to be a GPCR agonist, induces GRK5, normally activated by a GPCR, such as the 2-adrenergic receptor ( Figure 5) [8,11], to phosphorylate and inhibit the MR in the cytosol of a cardiac myocyte. Nevertheless, these salient questions will be the focus of our future investigations, along with our already ongoing efforts to map the specific In summary, our present study reinforces the emerging and therapeutically very intriguing notion that GRK5, acting as a cardiac MR co-repressor in this instance, may actually be beneficial in the myocardium [11,[31][32][33], contrary to its counterpart GRK2 that is generally considered deleterious in the heart [7,10]. Importantly, we have identified GRK5 as a potential co-factor of the cardiac MR that is differentially regulated by finerenone and eplerenone, which may underlie the higher potency/efficacy (and inverse agonism) of finerenone at the MR. To our knowledge, cardiac GRK5…”

Section: Discussionsupporting

confidence: 73%

“…GRK2 and GRK5 are the most abundant cardiac G protein-coupled receptor (GPCR)-kinase (GRK) isoforms. Both phosphorylate GPCRs but also non-GPCR substrates [6][7][8][9][10]. We recently showed that GRK5 blocks the cardio-toxic MR-dependent effects of aldosterone in the heart by directly phosphorylating the cardiac MR and inhibiting its transcriptional activity [11].…”

Section: Introductionmentioning

confidence: 99%

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GRK5 is an Essential Co-repressor for Cardiac Mineralocorticoid Receptor Antagonism induced by Finerenone but not Eplerenone

Desimine¹,

Ghandour²,

Cora³

et al. 2020

Preprint

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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 (GPCR)-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. Herein, we sought to investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade. Methods: We used the cardiomyocyte cell line H9c2 and neonatal rat ventricular myocytes (NRVMs). 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 in NRVMs, GRK5 is necessary for the anti-apoptotic 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 and fibrosis. 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. GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

GRK5 is an Essential Co-repressor for Cardiac Mineralocorticoid Receptor Antagonism induced by Finerenone but not Eplerenone

Desimine¹,

Ghandour²,

Cora³

et al. 2020

Preprint

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“…GRK2 and GRK5 are the most abundant isoforms in extraretinal tissues, and GRK2, cytoplasmic when inactive, requires interaction with the free Gβγ subunits of activated G proteins for activation/membrane translocation [9]. In contrast, GRK5 is ionically bound to cell membrane phospholipids via a highly basic region of its C-terminus, so it is usually cell membrane-anchored [31]. Notably, the MR was recently shown to promote heart failure by activating GRK2-dependent apoptosis and GRK5 nuclear accumulation-dependent hypertrophy in transgenic mouse hearts in vivo [30].…”

Section: Discussionmentioning

confidence: 99%

Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition

Maning

McCrink

Pollard

et al. 2020

IJMS

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Aldosterone (Aldo), when overproduced, is a cardiotoxic hormone underlying heart failure and hypertension. Aldo exerts damaging effects via the mineralocorticoid receptor (MR) but also activates the antiapoptotic G protein-coupled estrogen receptor (GPER) in the heart. G protein-coupled receptor (GPCR)-kinase (GRK)-2 and -5 are the most abundant cardiac GRKs and phosphorylate GPCRs as well as non-GPCR substrates. Herein, we investigated whether they phosphorylate and regulate cardiac MR and GPER. To this end, we used the cardiomyocyte cell line H9c2 and adult rat ventricular myocytes (ARVMs), in which we manipulated GRK5 protein levels via clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and GRK2 activity via pharmacological inhibition. We report that GRK5 phosphorylates and inhibits the cardiac MR whereas GRK2 phosphorylates and desensitizes GPER. In H9c2 cardiomyocytes, GRK5 interacts with and phosphorylates the MR upon β2-adrenergic receptor (AR) activation. In contrast, GRK2 opposes agonist-activated GPER signaling. Importantly, GRK5-dependent MR phosphorylation of the MR inhibits transcriptional activity, since aldosterone-induced gene transcription is markedly suppressed in GRK5-overexpressing cardiomyocytes. Conversely, GRK5 gene deletion augments cardiac MR transcriptional activity. β2AR-stimulated GRK5 phosphorylates and inhibits the MR also in ARVMs. Additionally, GRK5 is necessary for the protective effects of the MR antagonist drug eplerenone against Aldo-induced apoptosis and oxidative stress in ARVMs. In conclusion, GRK5 blocks the cardiotoxic MR-dependent effects of Aldo in the heart, whereas GRK2 may hinder beneficial effects of Aldo through GPER. Thus, cardiac GRK5 stimulation (e.g., via β2AR activation) might be of therapeutic value for heart disease treatment via boosting the efficacy of MR antagonists against Aldo-mediated cardiac injury.

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“…One of the most powerful physiological stimuli for the synthesis and secretion of aldosterone, and the last step in the renin-angiotensin-aldosterone system axis, is angiotensin II activation of the AT 1 R, a G q/11 protein-coupled receptor [57,58,59,60,61]. Specifically, the AT 1 R promotes aldosterone production in the adrenal cortex through G q/11 protein, i.e., diacylglycerol (DAG) and inositol trisphosphate (IP 3 ) signaling, but also through βarrestin1 signaling to extracellular signal-regulated kinases (ERK)-dependent steroidogenic acute regulatory (StAR) protein upregulation [62,63,64,65,66].…”

Section: Gpcr Signaling and Mr Functionmentioning

confidence: 99%

Novel Insights into the Crosstalk between Mineralocorticoid Receptor and G Protein-Coupled Receptors in Heart Adverse Remodeling and Disease

Parker

Wertz

Pollard

et al. 2018

IJMS

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The mineralocorticoid hormone aldosterone regulates sodium and potassium homeostasis but also adversely modulates the maladaptive process of cardiac adverse remodeling post-myocardial infarction. Through activation of its mineralocorticoid receptor (MR), a classic steroid hormone receptor/transcription factor, aldosterone promotes inflammation and fibrosis of the heart, the vasculature, and the kidneys. This is why MR antagonists reduce morbidity and mortality of heart disease patients and are part of the mainstay pharmacotherapy of advanced human heart failure. A plethora of animal studies using cell type–specific targeting of the MR gene have established the importance of MR signaling and function in cardiac myocytes, vascular endothelial and smooth muscle cells, renal cells, and macrophages. In terms of its signaling properties, the MR is distinct from nuclear receptors in that it has, in reality, two physiological hormonal agonists: not only aldosterone but also cortisol. In fact, in several tissues, including in the myocardium, cortisol is the primary hormone activating the MR. There is a considerable amount of evidence indicating that the effects of the MR in each tissue expressing it depend on tissue- and ligand-specific engagement of molecular co-regulators that either activate or suppress its transcriptional activity. Identification of these co-regulators for every ligand that interacts with the MR in the heart (and in other tissues) is of utmost importance therapeutically, since it can not only help elucidate fully the pathophysiological ramifications of the cardiac MR’s actions, but also help design and develop novel better MR antagonist drugs for heart disease therapy. Among the various proteins the MR interacts with are molecules involved in cardiac G protein-coupled receptor (GPCR) signaling. This results in a significant amount of crosstalk between GPCRs and the MR, which can affect the latter’s activity dramatically in the heart and in other cardiovascular tissues. This review summarizes the current experimental evidence for this GPCR-MR crosstalk in the heart and discusses its pathophysiological implications for cardiac adverse remodeling as well as for heart disease therapy. Novel findings revealing non-conventional roles of GPCR signaling molecules, specifically of GPCR-kinase (GRK)-5, in cardiac MR regulation are also highlighted.

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Current and future G protein-coupled receptor signaling targets for heart failure therapy

Cited by 20 publications

References 105 publications

GRK5 is an Essential Co-repressor for Cardiac Mineralocorticoid Receptor Antagonism induced by Finerenone but not Eplerenone

GRK5 is an Essential Co-repressor for Cardiac Mineralocorticoid Receptor Antagonism induced by Finerenone but not Eplerenone

Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition

Novel Insights into the Crosstalk between Mineralocorticoid Receptor and G Protein-Coupled Receptors in Heart Adverse Remodeling and Disease

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