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J Biol Chem. 2019 Aug 23;294(34):12846-12854. doi: 10.1074/jbc.RA119.008330. Epub 2019 Jul 12.

Inflammasome inhibition blocks cardiac glycoside cell toxicity.

Author information

1
Department of Pediatrics, University of California San Diego, La Jolla, California 92093.
2
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093.
3
Department of Microbiology and Immunology, Emory School of Medicine, Atlanta, Georgia.
4
Department of Medicine, Emory School of Medicine, Atlanta, Georgia 30322.
5
Institut Supérieur de la Santé et des Bioproduits, Angers, France 49000.
6
Department of Cardiovascular Medicine, University of California San Diego, La Jolla, California 92093.
7
Department of Pediatrics, University of California San Diego, La Jolla, California 92093 vnizet@ucsd.edu.
8
Department of Pediatrics, University of California San Diego, La Jolla, California 92093 christopher.larock@emory.edu.

Abstract

Chronic heart failure and cardiac arrhythmias have high morbidity and mortality, and drugs for the prevention and management of these diseases are a large part of the pharmaceutical market. Among these drugs are plant-derived cardiac glycosides, which have been used by various cultures over millennia as both medicines and poisons. We report that digoxin and related compounds activate the NLRP3 inflammasome in macrophages and cardiomyocytes at concentrations achievable during clinical use. Inflammasome activation initiates the maturation and release of the inflammatory cytokine IL-1β and the programmed cell death pathway pyroptosis in a caspase-1-dependent manner. Notably, the same fluxes of potassium and calcium cations that affect heart contraction also induce inflammasome activation in human but not murine cells. Pharmaceuticals that antagonize these fluxes, including glyburide and verapamil, also inhibit inflammasome activation by cardiac glycosides. Cardiac glycoside-induced cellular cytotoxicity and IL-1β signaling are likewise antagonized by inhibitors of the NLRP3 inflammasome or the IL-1 receptor-targeting biological agent anakinra. Our results inform on the molecular mechanism by which the inflammasome integrates the diverse signals that activate it through secondary signals like cation flux. Furthermore, this mechanism suggests a contribution of the inflammasome to the toxicity and adverse events associated with cardiac glycosides use in humans and that targeted anti-inflammatories could provide an additional adjunct therapeutic countermeasure.

KEYWORDS:

IL-1; cardiac glycoside; cardiomyocyte; caspase 1 (CASP1); cell death; inflammasome; macrophage

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