Development of novel agents using the method of modulating the transcriptional activity of apo (a) gene

点击翻译按钮获取中文摘要

Increased lipoprotein (Lp)(a) level is an independent risk factor for atheroscrelotic diseases and is observed in a frequency of 10〜15% in Japanese population. At present, there is few clinically effective agents with less adverse effects. We have developed a novel assay system in which a 1.4 kb in length of promoter region of apolipoprotein (apo)(a) is ligated in 5' end of luciferase plasmid. Among several agents we examined, we found that aspirin reduced luciferase activity in HepG2 cells and also suppressed mRNA expression of apo (a) in human hepatocytes. In vitro examination showed that aspirin decreased apo (a) production from hepatocytes by 30%. Based on these findings, we analyzed the effect of aspirin on serum Lp (a) levels in patients with atherosclerotic diseases and found that aspirin reduced Lp (a) levels by 20% in patients with high Lp (a) levels (more than 30 mg/dl) but not with normal Lp (a) levels (less than 30 mg/dl). Furthermore, the values of decrease in serum Lp (a) by aspirin in patients with high Lp (a) were positively correlated with the baseline Lp (a) levels. The difference of serum Lp (a) levels in patients containing same apo (a) isoform sizes is considered to be due to the difference of the transcriptional activity of apo (a) gene. Therefore, aspirin lowers serum Lp (a) levels in patients with high Lp (a) potentially via the reduction of apo (a) gene transcription.We next aimed to reveal the novel action of aspirin on the reduction of high Lp (a) levels via an independent mechanism from arachidonate pathway. Using enhanced subtractional hybridization analysis, we found a new nuclear factor with unknown function and are examining the effect of activation on the expression levels of apo (a).