Use Of Animal Models To Study Genes That Modulate Atherosclerosis

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In the past year, we have made several new transgenic mice lines to investigate the role of LCAT in cholesterol metabolism and atherosclerosis. hapoA-I and hLCAT transgenic mice each were found to have a modest 50% increase in HDL-C. This is consistent with the known role of apoA-I as the main structural protein of HDL and with the known role of LCAT in esterifying cholesterol, which allows the maturation of HDL into a spherical choleseryl ester rich particle. When hapoA-I and hLCAT transgenic mice were crossed, over a 10-fold increase in HDL-C was observed. This suggests that under normal circumstances, LCAT may not be that rate-limiting in the maturation of HDL, but in the presence of excess apoA-I, as in the apoA-I transgenic mice, it may be rate limiting. This finding suggests that the effectiveness of acute HDL replacement therapy, which involves the intravenous infusion of apoA-I associated with phospholipids, can potentially be improved by the co-administration of recombinant LCAT. In a series of mouse infusion studies in which recombinant apoA-I, recombinant LCAT were singly or co-infused, we found that the administered HDL was more effective in the presence of infused LCAT in mobilizing excess cholesterol from peripheral tissues and in the esterification of the removed cholesterol, which promotes the hepatic excretion of cholesterol. Future studies to examine the co-infusion of apoA-I and LCAT will be tested in animal models of atherosclerosis.