Cardiac glycosides potently inhibit C-reactive protein synthesis in human hepatocytes.
Elevated plasma levels of C-reactive protein (CRP), the prototype acute-phase protein (APP), are predictive for future cardiovascular events. Controversial evidence suggests that CRP may play a causal role in cardiovascular disease. CRP synthesis inhibition is a potential approach for reducing cardiovascular mortality. We show here that endogenous and plant-derived inhibitors of the Na(+)/K(+)-ATPase, i.e. the cardiac glycosides ouabain and digitoxin, inhibit IL-1beta- and IL-6-induced APP expression in human hepatoma cells and primary human hepatocytes (PHH) at nanomolar concentrations. Inhibition is demonstrated on transcriptional and on protein level. The molecular target of cardiac glycosides, i.e. the alpha1 subunit of the Na(+)/K(+)-ATPase, is strongly expressed in human hepatocytes. Inhibition of APP synthesis correlates with the potency of cardiac glycosides at the Na(+)/K(+)-ATPase. The trigger for APP expression inhibition is an increase in intracellular calcium since the calcium ionophore calcimycin is also active. Qualified specificity of oubain for hepatocellular APP synthesis inhibition is demonstrated by lack of effectivity on IL-1beta-induced IL-6 release from primary human coronary artery smooth muscle cells. The inhibitory activity of cardiac glycosides on CRP expression may have important implications for the treatment of cardiovascular disease. Cardiac glycosides may be used for CRP synthesis inhibition in the future.
Kolkhof
Peter
P
Global Drug Discovery, BAYER HealthCare, Wuppertal, Germany.
Geerts
Andreas
A
Schäfer
Stefan
S
Torzewski
Jan
J
D000328:Adult; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002301:Cardiac Glycosides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004074:Digitoxin / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010042:Ouabain / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*
D002301:Cardiac Glycosides; D053583:Interleukin-1beta; D015850:Interleukin-6; D010042:Ouabain; D002097:C-Reactive Protein; D004074:Digitoxin; D002118:Calcium