title: Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes.
abstract: 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 the present study we found that they increase the expression and activity of 3-hydroxy-3 methylglutaryl-CoA 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 (ATP-binding cassette protein A1) 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, digoxin and ouabain simultaneously 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 (high-density lipoprotein) cholesterol. The results of the present study suggest that cardioactive glycosides may have a role in the reverse transport of cholesterol and in the energy metabolism of cardiomyocytes.
authors: Department of Genetics, Biology and Biochemistry, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
authors: Ivana
authors: I
authors: Campia
authors: Valentina
authors: V
authors: Sala
authors: Joanna
authors: J
authors: Kopecka
authors: Christian
authors: C
authors: Leo
authors: Nico
authors: N
authors: Mitro
authors: Costanzo
authors: C
authors: Costamagna
authors: Donatella
authors: D
authors: Caruso
authors: Gianpiero
authors: G
authors: Pescarmona
authors: Tiziana
authors: T
authors: Crepaldi
authors: Dario
authors: D
authors: Ghigo
authors: Amalia
authors: A
authors: Bosia
authors: Chiara
authors: C
authors: Riganti
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis*; D004077:Digoxin / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000502:physiology*; D010042:Ouabain / Q000494:pharmacology*; D051381:Rats; D014451:Ubiquinone / Q000096:biosynthesis
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D014451:Ubiquinone; D010042:Ouabain; D004077:Digoxin; D000255:Adenosine Triphosphate; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid