Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Cardiol. May 26, 2020; 12(5): 192-202
Published online May 26, 2020. doi: 10.4330/wjc.v12.i5.192
Nicotine-induced adrenal beta-arrestin1 upregulation mediates tobacco-related hyperaldosteronism leading to cardiac dysfunction
Natalie Cora, Jennifer Ghandour, Celina Marie Pollard, Victoria Lynn Desimine, Krysten Elaine Ferraino, Janelle Marie Pereyra, Rachel Valiente, Anastasios Lymperopoulos
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 Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, United States
Author contributions: Cora N, Ghandour J, Pollard CM, Desimine VL, Ferraino KE, Pereyra JM, and Valiente R performed all the experiments and assisted with data analysis; Lymperopoulos A supervised the project, performed data analysis, provided funding for the study, and wrote the manuscript; all authors read and approved the final version of the article.
Supported by a Nova Southeastern University’s President’s Faculty Research and Development Grant award, No. 335467; and American Foundation for Pharmaceutical Research Gateway to Research Grant, No. 2017-333325 (both to Lymperopoulos A).
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals (NSU IACUC licence No. 013-398-09-0820, The Institutional Animal Care and Use Committee at MedImmune, Gaitherburg, MD, United States).
Conflict-of-interest statement: The authors have nothing to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Anastasios Lymperopoulos, BPharm, FAHA, MSc, PhD, Associate Professor, Director, Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy, Nova Southeastern University, 3200 S. University Dr., HPD (Terry) Bldg/Room 1350, Fort Lauderdale, FL 33328-2018, United States. al806@nova.edu
Received: January 3, 2020
Peer-review started: January 3, 2020
First decision: February 19, 2020
Revised: March 27, 2020
Accepted: May 12, 2020
Article in press: May 12, 2020
Published online: May 26, 2020
Abstract
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 two βarrestins (βarrestin1 and-2).

AIM

Since adrenal ßarrestin1 is essential for adrenal aldosterone production and nicotine/cotinine elevate circulating aldosterone levels in humans, we hypothesized that nicotine activates adrenal ßarrestin1, which contributes to RAAS activation and heart disease development.

METHODS

We studied human adrenocortical zona glomerulosa H295R cells and found that nicotine and cotinine upregulate βarrestin1 mRNA and protein levels, thereby enhancing AngII-dependent aldosterone synthesis and secretion.

RESULTS

In contrast, siRNA-mediated βarrestin1 knockdown reversed the effects of nicotine on AngII-induced aldosterone production in H295R cells. Importantly, nicotine promotes hyperaldosteronism via adrenal βarrestin1, thereby precipitating cardiac dysfunction, also in vivo, since nicotine-exposed experimental rats with adrenal-specific βarrestin1 knockdown display lower circulating aldosterone levels and better cardiac function than nicotine-exposed control animals with normal adrenal βarrestin1 expression.

CONCLUSION

Adrenal βarrestin1 upregulation is one of the mechanisms by which tobacco compounds, like nicotine, promote cardio-toxic hyperaldosteronism in vitro and in vivo. Thus, adrenal βarrestin1 represents a novel therapeutic target for tobacco-related heart disease prevention or mitigation.

Keywords: Adrenocortical zona glomerulosa cell, Aldosterone, βarrestin, Nicotine, Signal transduction, Tobacco-related heart disease

Core tip: Adrenal βarrestin1 is a novel molecular target for mitigation of the aldosterone-dependent cardiotoxic effects of tobacco. Angiotensin II induces aldosterone production in adrenocortical zona glomerulosa (AZG) cells by binding to its adrenal angiotensin II type 1 receptor, which then activates βarrestin1. Nicotine and cotinine are known to activate the renin-angiotensin-aldosterone-system (RAAS), promoting hyperaldosteronism. We report herein that these main tobacco compounds chronically upregulate adrenal βarrestin1, promoting excessive aldosterone synthesis and secretion from human AZG cells in vitro and from adrenal glands in vivo. Thus, adrenal βarrestin1 critically mediates tobacco-induced RAAS activation, which contributes to heart disease development/progression.