Background: Increased serum lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis. We previously reported that aspirin reduced Lp(a) production by cultured hepatocytes via the reduction of apolipoprotein(a) [apo(a)] gene transcription. Methods: We evaluated both the effect of aspirin treatment (81 mg/day) on serum Lp(a) concentrations and the correlation between the degree of reduction in serum Lp(a) and the type of apo(a) isoform in 70 patients with coronary artery disease or cerebral infarction. Results: Aspirin lowered serum Lp(a) concentrations to ∼80% of the baseline values in patients with high Lp(a) concentrations (>300 mg/L). The percentage of decrease in serum Lp(a) was larger in patients with high Lp(a) than in patients with low Lp(a) (<300 mg/L), irrespective of apo(a) isoform size. The decreases in serum Lp(a) in high Lp(a) patients with both the high-molecular-weight and the low-molecular-weight isoforms were positively correlated with the baseline Lp(a) concentrations. Conclusions: Because the secretory efficiencies of apo(a) in the same isoform are likely to be similar, the difference in serum Lp(a) concentrations in patients having the same apo(a) isoform depends on the transcriptional activity of the apo(a) gene. These findings suggest that aspirin decreases serum Lp(a) concentrations via a decrease in apo(a) gene transcription more effectively in patients with high transcriptional activity of this gene.

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 dosedependent 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 M) 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. Lipoprotein(a) (Lp(a))1 is an low density lipoprotein-like lipoprotein in which apolipoprotein B-100 is disulfide-linked to an additional high molecular weight glycoprotein, apolipoprotein(a) (apo(a)) (1). Lp(a) has been shown to be deposited in atherosclerotic plaques (2-4). Because apo(a) is highly homologous to plasminogen (5), it competes with plasminogen for binding to its receptor, resulting in the inhibition of plasmin formation (6, 7) and transforming growth factor-␤ activation (8, 9). These properties of Lp(a) lead to retardation of clot lysis and acceleration of cell growth. Serum Lp(a) level is strongly influenced by genetic backgrounds and is not influenced by age, foods, or environmental conditions (10). However, in several disease states such as inflammatory disorders, serum Lp(a) levels are elevated (11). Epidemiological studies demonstrated that patients with cardiovascular or cerebrovascular diseases show higher serum Lp(a) levels (12, 13), and that elevated serum Lp(a) is an independent risk factor for coronary heart disease in both men and women aged 55 years and younger (14, 15). It has been reported that nicotinic acid can lower serum Lp(a) levels by as much as 38% (16), although several adverse effects by this agent hampers general clinical use for patients with high serum Lp(a) levels.Aspirin has been used widely in patients with atherosclerotic diseases, and its efficacy in preventing coronary heart disease has been established. Although the effect of aspirin is thought to be mainly due to an inhibition of platelet aggreg...