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Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes
- Source :
- The Biochemical journal. 447(2)
- Publication Year :
- 2012
-
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.
- Subjects :
- Male
medicine.medical_specialty
Digoxin
Ubiquinone
Mevalonic Acid
Mevalonic acid
Biochemistry
Ouabain
Cell Line
Electron Transport
chemistry.chemical_compound
Mice
Adenosine Triphosphate
Internal medicine
medicine
Animals
Myocytes, Cardiac
Liver X receptor
Molecular Biology
Liver X Receptors
biology
Apolipoprotein A-I
Cholesterol
Cell Biology
Orphan Nuclear Receptors
Rats
Mitochondrial respiratory chain
ATP Binding Cassette Transporter 1
Endocrinology
chemistry
ABCA1
biology.protein
lipids (amino acids, peptides, and proteins)
ATP-Binding Cassette Transporters
Hydroxymethylglutaryl CoA Reductases
Lipoproteins, HDL
Lipoprotein
medicine.drug
Subjects
Details
- ISSN :
- 14708728
- Volume :
- 447
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- The Biochemical journal
- Accession number :
- edsair.doi.dedup.....9a9aa37e029ce753020b715fc177f59b