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
Processing time: 143 Days and 9.7 Hours
ARTICLE HIGHLIGHTS
Research background

Nicotine, the main addictive compound in tobacco, is associated with major cardiovascular adverse events, such as heart failure and hypertension. One of the molecular mechanisms underlying nicotine-induced cardiotoxicity is elevation of renin-angiotensin-aldosterone system (RAAS) activity. Nicotine, and its major metabolite in humans cotinine, have been reported to induce RAAS activation, resulting in hyperaldosteronism. Aldosterone has myriad adverse cardiac effects and is produced by the adrenal cortex in response to angiotensin II (AngII) acting through its type 1 receptors (AT1Rs). AT1Rs induce aldosterone production via both Gq/11 proteins and βarrestin1 (Arrestin-2).

Research motivation

It was hypothesized that nicotine activates adrenal ßarrestin1, thereby contributing to RAAS activation and heart disease development.

Research objectives

We tested our hypothesis by investigating the effects of nicotine on aldosterone production in vitro and on aldosterone levels and cardiac function of experimental animals in vivo.

Research methods

We used the human adrenocortical zona glomerulosa (AZG) cell line H295R, in which we performed real-time polymerase chain reaction (PCR) and western blotting to measure βarrestin1 mRNA and protein levels, respectively, as well as ELISA to measure aldosterone secretion. We also manipulated βarrestin1 expression via siRNA-mediated knockdown in H295R cells. For the in vivo studies, we used adult male Sprague-Dawley rats, which we exposed to chronic nicotine administration after adrenal-specific, βarrestin1 siRNA-mediated knockdown or control scrambled siRNA delivery in vivo.

Research results

Nicotine and cotinine upregulate βarrestin1 mRNA and protein levels in AZG cells, which augments aldosterone synthesis and secretion. In contrast, siRNA-mediated βarrestin1 knockdown mitigates the effects of nicotine on AngII-induced aldosterone production. In vivo, 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.

Research conclusions

Adrenal βarrestin1 upregulation is one of the mechanisms by which tobacco, i.e. nicotine, promotes cardio-toxic hyperaldosteronism that accelerates cardiac functional decline, both in vitro and in vivo.

Research perspectives

Adrenal βarrestin1 pharmacological blockade or genetic deletion (or knockdown) represents a novel therapeutic strategy to ameliorate tobacco-related heart disease morbidity and mortality.