Pharmacological effects of cardiac glycosides on cell death and autophagy: Impact on the mitochondrial network structure and function

Abstract

By 2030, 43.9% of the US adult population is projected to have some form of cardiovascular disease (CVD) highlighting the need for new therapeutic strategy or an improvement of existing treatments. In many cardiac diseases (i.e. heart failure, myocardial infarction, ischemia/reperfusion), mitochondria can receive harmful signals, dysfunction and then, participate actively in the pathogenesis. They can undergo either a decrease of their bioenergetic capacity, a process called mitochondrial permeability transition which leads to cell death, alterations of mitochondrial protein expression patterns or perturbations in the fusion/fission balance. In a cardioprotective perspective, it is important to evaluate the effect of drugs on mitochondrial structure and function, because this can impact on cardiac function and health at a more general level. In this context, we evaluated the mitochondrial effects of Digoxine and Digitoxigenine, two cardiac glycosides used in clinics for heart failure treatment. We selected these two compounds in a high throughput screening of cell death inhibitors revealing their activity as potent inhibitors of apoptosis and necrosis of cardiomyoblasts. We confirmed their activity in rat neonatal ventricular cardiomyocytes and showed their capacity to induce autophagy. We also analysed their effects on mitochondrial network structure by fluorescent confocal microscopy and on bioenergetics by Seahorse technology. Our study offers new insights into the pharmacological effects of cardiac glycosides that could help to better understand their mechanisms of cardioprotection.