Establishment of a new antiatherosclerotic drug and its screening methods using an animal model.

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In order to establish the screening methods for anti-atherosclerotic drug, we could develop the primary culture system for rabbit hepatic cells as reported last year. In addition when we added collagens in the culture medium, we found that rabbit hepatic cells could easily attach to the dish. This finding makes our experiments to be done easily.As reported last year, pravastatin, an inhibitor of HMG-CoA reductase inhibitor, induced the expression of LDL receptor in hepatic cells. Moreover, we found that pravastatin decreased apo B secretion significantly from the liver. On the other hand, when we incubated hepatic cells with LDL, 'hepatic cells secreted apo B more than that of control cells. When we added pravastatin to the cells, cellular cholesteryl ester was decreased. Therefore these results indicated that the change of apo B secretion was in parallel with the change of cellular cholesteryl ester contents. Furthermore we investigated intracellular degradation of apo B prior to secretion and found that the addition of pravastatin accelerated intracellular degradation of apo B, while LDL slowed apo B intracellular degradation rate. However the change of cellular cholesteryl ester could not affect apo B mRNA levels, examined by northen blot analysis.We conclude that intracellular cholesteryl ester contents play a critical role for apo B secretion and intracellular apo B degradation rate could be the main mechanism that regulated apo B secretion in response to the change of intracellular cholesteryl ester level. We are investigating the detail mechanism of these findings.Finally it is still very difficult to make new compounds which have at least two activities, such as an inhibitor of HMG-CoA reductase and an antioxidant action. This experiment is undergoing.