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

Title: Cardiac glycosides cause cytotoxicity in human macrophages and ameliorate white adipose tissue homeostasis
Authors: 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: 1-May-2022
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: 1874
End Page: 1886
Journal / Book Title: British Journal of Pharmacology
Volume: 179
Issue: 9
Copyright Statement: © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Wellcome Trust
Medical Research Council (MRC)
Funder's Grant Number: MR/N01121X/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
cardiac glycosides
cell death
white adipose tissue
cardiac glycosides
cell death
white adipose tissue
Pharmacology & Pharmacy
1115 Pharmacology and Pharmaceutical Sciences
Publication Status: Published
Online Publication Date: 2021-03-04
Appears in Collections:Department of Immunology and Inflammation
Department of Infectious Diseases
Institute of Clinical Sciences
Faculty of Medicine
Department of Brain Sciences