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.
Highlights
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
We report that digoxin and other cardiac glycosides potently activate the inflammasome in human cells, including cardiomyocytes
Cytotoxicity has been reported previously for several cardiac glycosides, with reported IC50 values ranging from low nanomolar to high micromolar and the mechanism of cell death varyingly described as apoptosis, necrosis, pyroptosis, or unknown [15, 18]
Summary
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. Ingestion of wild or ornamental plants containing cardiac glycosides, including lily of the valley, foxglove, and oleander, can lead to lethal intoxication and is a common choice for intentional self-poisoning throughout the world [5] These compounds can be therapeutically useful, and cardiac glycosides have been used to treat heart conditions for centuries, as documented by use of foxglove by the 18thcentury botanist and physician William Withering (digitalis/ digoxin) [6]. Intoxication is a common and serious adverse event observed across numerous clinical trials, and a long-standing controversy has been whether their continued use is justified [7,8,9,10] Their low cost has made them attractive for the management of rheumatic heart disease induced by group A Streptococcus, which is most prevalent in resource-poor countries, but the potential therapeutic benefit may be associated with increased mortality [11]. This sensitivity exceeds that reported previously in mice [14], mirroring the known species-specific susceptibility of the Na,K-ATPase car-
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