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Cardiac glycosides cause cytotoxicity in human macrophages and ameliorate white adipose tissue homeostasis

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Title: Cardiac glycosides cause cytotoxicity in human macrophages and ameliorate white adipose tissue homeostasis
Authors: Behmoaras, J
Olona, A
Hateley, C
Guerrero, A
Ko, J-H
Johnson, MR
Anand, PK
Thomas, D
Gil, J
Behmoaras, J
Item Type: Journal Article
Abstract: Background and purpose: Cardiac glycosides (CGs) inhibit the Na+,K+‐ATPase and are widely prescribed medicines for chronic heart failure and cardiac arrhythmias. Recently, CGs have been described to induce inflammasome activation and pyroptosis in human macrophages, suggesting a cytotoxicity that remains to be elucidated in tissues. Experimental approach: To determine the cell type specificity of CG‐mediated cytotoxicity, we used human primary monocyte‐derived macrophages (hMDMs) and non‐adherent peripheral blood cells isolated from healthy donors. Omental white adipose tissue (WAT) and stromal vascular fraction (SVF)‐derived pre‐adipocytes and adipocytes were isolated from obese patients undergoing bariatric surgery. All these primary cells/tissues were treated with nanomolar concentrations of ouabain (50nM, 100nM and 500nM) to investigate its degree of cytotoxicity and mechanisms leading to cell death. In WAT, we further explored the consequences of ouabain‐mediated cytotoxicity by measuring insulin sensitivity, adipose tissue function and extracellular matrix (ECM) deposition ex vivo. Key results: The ouabain‐induced cell death is through pyroptosis and apoptosis, and more efficient in hMDMs compared to non‐adherent PBMC populations. This selective cytotoxicity is dependent on K+ flux, as ouabain causes an intracellular depletion of K+, while inducing accumulation of Na+ and Ca2+ levels. Consistently, the cell‐death caused by these ion imbalances can be rescued by addition of potassium chloride in hMDMs. Remarkably, when WAT explants from obese patients are cultured with nanomolar concentrations of ouabain, this causes depletion of macrophages, down‐regulation of type VI collagen levels, and amelioration of insulin sensitivity ex vivo. Conclusions and implications: These results suggest that the usage of nanomolar concentration of CGs can be an attractive therapeutic avenue in metabolic syndrome characterised by pathogenic infiltration and activation of macrophages.
Issue Date: 4-Mar-2021
Date of Acceptance: 5-Feb-2021
URI: http://hdl.handle.net/10044/1/87810
DOI: 10.1111/bph.15423
ISSN: 0007-1188
Publisher: Wiley
Start Page: 1
End Page: 1
Journal / Book Title: British Journal of Pharmacology
Copyright Statement: © 2021 The Author(s). This is the accepted version of the following article: Olona, A. et al, Cardiac glycosides cause cytotoxicity in human macrophages and ameliorate white adipose tissue homeostasis, British Journal of Pharmacology, 4 March 2021, which will be published in final form at https://doi.org/10.1111/bph.15423
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Wellcome Trust
Funder's Grant Number: MR/N01121X/1
MR/V027638/1
EP/V520354/1
206617/A/17/Z
Keywords: Pharmacology & Pharmacy
1115 Pharmacology and Pharmaceutical Sciences
Publication Status: Published online
Embargo Date: Embargoed for 12 months after publication date
Online Publication Date: 2021-03-04
Appears in Collections:Department of Immunology and Inflammation
Department of Infectious Diseases
Institute of Clinical Sciences
Department of Brain Sciences