Imperial College London
Alternate

Dr Paras Anand

Faculty of Medicine, Department of Infectious Disease

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 3313 2063paras.anand Website

 
 
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Location

 

8.N23Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Olona:2022:10.1111/bph.15423,
author = {Olona, A and Hateley, C and Guerrero, A and Ko, J-H and Johnson, MR and Anand, PK and Thomas, D and Gil, J and Behmoaras, J},
doi = {10.1111/bph.15423},
journal = {British Journal of Pharmacology},
pages = {1874--1886},
title = {Cardiac glycosides cause cytotoxicity in human macrophages and ameliorate white adipose tissue homeostasis},
url = {http://dx.doi.org/10.1111/bph.15423},
volume = {179},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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 CGmediated cytotoxicity, we used human primary monocytederived macrophages (hMDMs) and nonadherent peripheral blood cells isolated from healthy donors. Omental white adipose tissue (WAT) and stromal vascular fraction (SVF)derived preadipocytes 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 ouabainmediated cytotoxicity by measuring insulin sensitivity, adipose tissue function and extracellular matrix (ECM) deposition ex vivo.Key results: The ouabaininduced cell death is through pyroptosis and apoptosis, and more efficient in hMDMs compared to nonadherent 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 celldeath 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, downregulation 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.
AU  - Olona,A
AU  - Hateley,C
AU  - Guerrero,A
AU  - Ko,J-H
AU  - Johnson,MR
AU  - Anand,PK
AU  - Thomas,D
AU  - Gil,J
AU  - Behmoaras,J
DO  - 10.1111/bph.15423
EP  - 1886
PY  - 2022///
SN  - 0007-1188
SP  - 1874
TI  - Cardiac glycosides cause cytotoxicity in human macrophages and ameliorate white adipose tissue homeostasis
T2  - British Journal of Pharmacology
UR  - http://dx.doi.org/10.1111/bph.15423
UR  - https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15423
UR  - http://hdl.handle.net/10044/1/87810
VL  - 179
ER  -
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