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

作　　者：Natalie Cora Jennifer Ghandour Celina Marie Pollard Victoria Lynn Desimine Krysten Elaine Ferraino Janelle Marie Pereyra Rachel Valiente Anastasios Lymperopoulos 

机构地区：[1]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

出　　处：《World Journal of Cardiology》2020年第5期192-202,共11页世界心脏病学杂志（英文版）（电子版）

基　　金：Supported by a Nova Southeastern University’s President’s Faculty Research and Development Grant award,No.335467;American Foundation for Pharmaceutical Research Gateway to Research Grant No.2017-333325(both to Lymperopoulos A)。

摘　　要：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,promot

关 键 词：Adrenocortical zona glomerulosa cell Aldosterone βarrestin NICOTINE Signal transduction Tobacco-related heart disease 

分 类 号：R541[医药卫生—心血管疾病]