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| 1 | Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure therapy显示文摘Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II(Ang II). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure(HF), is induced by Ang II type 1 receptors(AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1(βarr1) or-2(βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 proteinindependent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers(ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes(G protein-, and βarr1-dependent) at the Ang IIactivated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by Ang II and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-'biased' blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan(and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone. | Anastasios Lymperopoulos Beatrix Aukszi | 2017 | World Journal of Cardiology2017，9，3： | 11 |
| 2 | Adrenal G protein-coupled receptor kinase-2 in regulation of sympathetic nervous system activity in heart failure显示文摘Heart failure(HF), the number one cause of death in the western world, is caused by the insufficient performance of the heart leading to tissue underperfusion in response to an injury or insult. It comprises complex interactions between important neurohormonal mechanisms that try but ultimately fail to sustain cardiac output. The most prominent such mechanism is the sympathetic(adrenergic) nervous system(SNS), whose activity and outflow are greatly elevated in HF. SNS hyperactivity confers significant toxicity to the failing heart and markedly increases HF morbidity and mortality via excessive activation of adrenergic receptors, which are G protein-coupled receptors. Thus, ligand binding induces their coupling to heterotrimeric G proteins that transduce intracellular signals. G protein signaling is turned-off by the agonist-bound receptor phosphorylation courtesy of G protein-coupled receptor kinases(GRKs), followed by βarrestin binding, which prevents the GRK-phosphorylated receptor from further interaction with the G proteins and simultaneously leads it inside the cell(receptor sequestration). Recent evidence indicates that adrenal GRK2 and βarrestins can regulate adrenal catecholamine secretion, thereby modulating SNS activity in HF. The present review gives an account of all these studies on adrenal GRKs and βarrestins in HF and discusses the exciting new therapeutic possibilities for chronic HF offered by targeting these proteins pharmacologically. | Katie A Mc Crink Ava Brill Anastasios Lymperopoulos | 2015 | World Journal of Cardiology2015，7，9： | 4 |
| 3 | Not all arrestins are created equal: Therapeutic implications of the functional diversity of the β-arrestins in the heart显示文摘The two ubiquitous, outside the retina, G protein-coupled receptor(GPCR)adapter proteins, β-arrestin-1 and-2(also known as arrestin-2 and-3,respectively), have three major functions in cells: GPCR desensitization, i.e.,receptor decoupling from G-proteins; GPCR internalization via clathrin-coated pits; and signal transduction independently of or in parallel to G-proteins. Bothβ-arrestins are expressed in the heart and regulate a large number of cardiac GPCRs. The latter constitute the single most commonly targeted receptor class by Food and Drug Administration-approved cardiovascular drugs, with about onethird of all currently used in the clinic medications affecting GPCR function.Since β-arrestin-1 and-2 play important roles in signaling and function of several GPCRs, in particular of adrenergic receptors and angiotensin II type 1 receptors,in cardiac myocytes, they have been a major focus of cardiac biology research in recent years. Perhaps the most significant realization coming out of their studies is that these two GPCR adapter proteins, initially thought of as functionally interchangeable, actually exert diametrically opposite effects in the mammalian myocardium. Specifically, the most abundant of the two β-arrestin-1 exerts overall detrimental effects on the heart, such as negative inotropy and promotion of adverse remodeling post-myocardial infarction(MI). In contrast, β-arrestin-2 is overall beneficial for the myocardium, as it has anti-apoptotic and antiinflammatory effects that result in attenuation of post-MI adverse remodeling,while promoting cardiac contractile function. Thus, design of novel cardiac GPCRligands that preferentially activate β-arrestin-2 over β-arrestin-1 has the potential of generating novel cardiovascular therapeutics for heart failure and other heart diseases. | Anastasios Lymperopoulos Shelby L Wertz Celina M Pollard Victoria L Desimine Jennifer Maning Katie A McCrink | 2019 | World Journal of Cardiology2019，11，2： | 1 |
| 4 | Nicotine-induced adrenal beta-arrestin1 upregulation mediates tobacco-related hyperaldosteronism leading to cardiac dysfunction显示文摘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 diseases.Among the mechanisms by which nicotine contributes to heart disease is elevation of the renin-angiotensin-aldosterone system(RAAS)activity.Nicotine,and its major metabolite in humans cotinine,have been reported to induce RAAS activation,resulting in aldosterone elevation in smokers.Aldosterone has various direct and indirect adverse cardiac effects.It is produced by the adrenal cortex in response to angiotensin II(AngII)activating AngII type 1 receptors.RAAS 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 development.METHODS 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 secretion.RESULTS In contrast,siRNA-mediatedβarrestin1 knockdown reversed the effects of nicotine on AngII-induced aldosterone production in H295 R cells.Importantly,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 expression.CONCLUSION Adrenalβarrestin1 upregulation is one of the mechanisms by which tobacco compounds,like nicotine,promote cardio-toxic hyperaldosteronism in vitro and in vivo.Thus,adrenalβarrestin1 represents a novel therapeutic target for tobaccorelated heart disease prevention or mitigation. | Natalie Cora Jennifer Ghandour Celina Marie Pollard Victoria Lynn Desimine Krysten Elaine Ferraino Janelle Marie Pereyra Rachel Valiente Anastasios Lymperopoulos | 2020 | World Journal of Cardiology2020，12，5： | 1 |
| 5 | Pharmacogenetics of cardiac inotropy显示文摘 | Anastasios Lymperopoulos Dilayda Garcia Karlee Walklett | 2014 | Pharmacogenomics2014，，14： | 1 |
| 6 | Negative Impact of β-Arrestin-1 on Post-Myocardial Infarction Heart Failure via Cardiac and Adrenal-Dependent Neurohormonal Mechanisms显示文摘 | Ashley Bathgate-Siryk Samalia Dabul Krunal Pandya Karlee Walklett Giuseppe Rengo Alessandro Cannavo Claudio De Lucia Daniela Liccardo Erhe Gao Dario Leosco Walter J. Koch Anastasios Lymperopoulos | 2014 | Hypertension2014，，2： | 1 |
| 7 | Adrenergic Nervous System in Heart Failure: Pathophysiology and Therapy显示文摘 | Anastasios Lymperopoulos Giuseppe Rengo Walter J. Koch | 2013 | Circulation Research2013，，6： | 1 |
| 8 | Arrestins in the Cardiovascular System显示文摘 | Anastasios Lymperopoulos Ashley Bathgate | 2013 | Progress in Molecular Biology and Translational Science2013，，： | 1 |
| 9 | Ischemic Emergency?: Endothelial Cells Have Their Own “Adrenaline Shot” at Hand显示文摘 | Anastasios Lymperopoulos | 2012 | Hypertension2012，，1： | 1 |
| 10 | Pharmacogenomics of the heptahelical receptor regulators G-protein-coupled receptor kinases and arrestins: the known and the unknown显示文摘 | Anastasios Lymperopoulos Ashley Bathgate | 2012 | Pharmacogenomics2012，，3： | 1 |
| 11 | GRK2 Inhibition in Heart Failure: Something Old, Something New显示文摘 | Anastasios Lymperopoulos Giuseppe Rengo Walter J. Koch | 2012 | Current Pharmaceutical Design2012，，2： | 1 |
| 12 | Adrenal Beta-Arrestin 1 Inhibition In Vivo Attenuates Post-Myocardial Infarction Progression to Heart Failure and Adverse Remodeling Via Reduction of Circulating Aldosterone Levels显示文摘 | Anastasios Lymperopoulos Giuseppe Rengo Carmela Zincarelli Jihee Kim Walter J. Koch | 2011 | Journal of the American College of Cardiology2011，，3： | 1 |
| 13 | GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone显示文摘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. | Celina M Pollard Malka S Suster Natalie Cora Alexandra M Carbone Anastasios Lymperopoulos | 2022 | World Journal of Cardiology2022，14，4： | 0 |
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