Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes

被引:26
作者
Campia, Ivana [1 ]
Sala, Valentina [2 ]
Kopecka, Joanna [1 ]
Leo, Christian [2 ]
Mitro, Nico [3 ]
Costamagna, Costanzo [1 ]
Caruso, Donatella [3 ]
Pescarmona, Gianpiero [1 ,4 ]
Crepaldi, Tiziana [2 ]
Ghigo, Dario [1 ]
Bosia, Amalia [1 ,4 ]
Riganti, Chiara [1 ,4 ]
机构
[1] Univ Turin, Dept Genet Biol & Biochem, I-10126 Turin, Italy
[2] Univ Turin, Dept Anat Pharmacol & Forens Med, I-10126 Turin, Italy
[3] Univ Milan, Dept Pharmacol & Biomol Sci, I-20133 Milan, Italy
[4] Univ Turin, Res Ctr Expt Med CeRMS, I-10126 Turin, Italy
关键词
ATP-binding cassette protein A1 (ABCA1); cholesterol; digoxin; liver X receptor; ubiquinone; CARDIAC-GLYCOSIDES; TRANSPORTER A1; COENZYME Q(10); CELL-LINE; BINDING; EXPRESSION; GENE; BIOSYNTHESIS; MECHANISM; PROTEIN;
D O I
10.1042/BJ20120200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:301 / 311
页数:11
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