Aspirin reduces apolipoprotein(a) (apo(a)) production in human hepatocytes by suppression of apo(a) gene transcription.
High serum lipoprotein(a) (Lp(a)) is a risk factor for vascular disorders. Our preliminary observations suggest that, in some patients with coronary heart disease with high serum Lp(a) levels, administration of aspirin reduced Lp(a) levels. Therefore, we aimed to analyze the effects of aspirin on the production of apo(a), the expression of apolipoprotein(a) (apo(a)) mRNA and the transcriptional activity of apo(a) gene promoter. Aspirin (5 mM) reduced the apo(a) levels in culture medium of human hepatocytes and suppressed apo(a) mRNA expression to 73% and 85% of the controls, respectively. Aspirin also reduced the transcriptional activity of apo(a) gene transfected into HepG2 hepatoma cells in a dose-dependent manner, with a maximal effect at 5 mM (44.3 +/- 1.5% of the control). Sodium salicylate (5 mM) also reduced apo(a) gene transcription, whereas indomethacin (10 microM) had no effect. Deletion analysis of apo(a) gene promoter showed that promoter region extending from -30 to +138 is critical for the effect of aspirin. Furthermore, enhanced production, mRNA expression, and gene transcription of apo(a) by interleukin-6 were also inhibited by aspirin. These results demonstrate that aspirin reduces apo(a) production from hepatocytes via reduction of the transcriptional activity of apo(a) gene with suppression of apo(a) mRNA expression. The suppression of apo(a) production by aspirin may at least in part play a role in the anti-atherogenic effect of aspirin in vascular disorders.
Kagawa
A
A
First Department of Internal Medicine, University of Tokushima School of Medicine, Kuramoto-cho 3, Tokushima 770-8503, Japan.
Azuma
H
H
Akaike
M
M
Kanagawa
Y
Y
Matsumoto
T
T
D001054:Apolipoproteins A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008156:Luciferases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012980:Sodium Salicylate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D001054:Apolipoproteins A; D015850:Interleukin-6; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D008156:Luciferases; D001241:Aspirin; D012980:Sodium Salicylate; D007213:Indomethacin