Digoxin and ouabain induce the efflux of cholesterol via LXR signalling and the synthesis of ATP in cardiomyocytes.

Cardioactive glycosides exert positive inotropic effects on cardiomyocytes, through the inhibition of Na+/K+ ATPase. We showed previously that in human hepatoma cells, digoxin and ouabain increase the rate of the mevalonate cascade and therefore have Na+/K+ ATPase-independent effects. In this work we found that they increase the expression and activity of 3-hydroxy-3 methyl glutaryl coenzyme A reductase and the synthesis of cholesterol in cardiomyocytes, their main target cells. Surprisingly this did not promote intracellular cholesterol accumulation. The glycosides activated the liver X receptor transcription factor and increased the expression of ABCA1 transporter, which mediates the efflux of cholesterol and its delivery to apolipoprotein A-I. By increasing the synthesis of ubiquinone, another derivative of the mevalonate cascade, at the same time digoxin and ouabain enhanced the rate of electron transport in the mitochondrial respiratory chain and the synthesis of ATP. Mice treated with digoxin showed lower cholesterol and higher ubiquinone content in their hearts, and a small increase in their serum HDL-cholesterol. Our results suggest that cardioactive glycosides may have a role in the reverse transport of cholesterol and in the energy metabolism of cardiomyocytes.