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Not all arrestins are created equal: Therapeutic implications of the functional diversity of the β-arrestins in the heart

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World Journal of Cardiology 2019年第2期11卷 47-56页

作者： Anastasios Lymperopoulos shelby L Wertz Celina M Pollard Victoria L Desimine Jennifer Maning Katie A McCrink Laboratory for the study of Neurohormonal Control of the Circulation Department of Pharmaceutical Sciences (Pharmacology) College of PharmacyNova Southeastern University Jackson Memorial Hospital Massachusetts General Hospital

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 *** 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.

关键词： Adverse remodeling β-arrestin Biased signaling Cardiac myocyte Cardiac fibroblast contractility Functional divergence G protein-coupled receptor Heart failure Hormone Myocardial infarction signal transducer

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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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