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

Abstract

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 in human macrophages, suggesting a cytotoxicity that remains to be elucidated in tissues. Here we show that human monocyte-derived macrophages (hMDMs) undergo cell death following incubation with nanomolar concentrations of CGs, and in particular with ouabain (IC50=50 nM). The ouabain-induced cell death is more efficient in hMDMs compared to non-adherent PBMC populations and is through on-target inhibition of Na,K-ATPAse activity, as it 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. Strikingly, white adipose tissue (WAT) explants from morbidly obese patients cultured with nanomolar concentrations of ouabain causes depletion of macrophages, decreases type VI collagen levels, and ameliorates insulin-sensitivity ex vivo. 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.

Similarities and interplay between senescent cells and macrophages

“…Cardiac glycosides such as digoxin and digitoxin show in situ senolytic activity at a nanomolar range concentration that is close to the one observed in cardiac patients treated with this drug ( Guerrero et al, 2019 ; López-Lázaro, 2007 ). We have observed that cardiac glycosides cause cytotoxicity in human macrophages and ameliorate homeostasis in white adipose tissue from obese patients ( Olona et al, 2020 ), raising the possibility that senolytics also cause selective cytotoxicity in mononuclear phagocytes. Tailoring these drugs for specifically one type of cell (macrophage or senescent cell) will require an in-depth knowledge of phenotypic similarities and interplay between macrophages and senescent cells.…”

Cellular senescence at the crossroads of inflammation and Alzheimer's disease

“…Macrophages and senescent cells share indeed many phenotypes, including lysosomal expansion, metabolic reprogramming, a secretory phenotype, phagocytic capacity and growth arrest [103]. Consequently, some senolytic drugs target macrophages resulting in therapeutic side-effects [67,104]. However, this senescence-like state in macrophages is reversible at least under certain circumstances [105].…”