Coronary artery disease (CAD) due to atherosclerosis is the leading cause of death and disability in our society. Plasma HDL cholesterol is the best available biochemical predictor of CAD. Low HDL levels are correlated with an increased incidence of premature CAD and high HDL levels are thought to be protective. Apolipoprotein Al (Apo Al) is the major protein constituent of HDL particles. Infusion of Apo Al into animals leads to an elevation in plasma levels of HDL. The timecourse for development of atherosclerosis makes it impractical to administer Apo Al by infusion however. We propose to use gene transfer techniques to test whether mice predisposed to atherosclerosis can be protected by over-expressing the gene for human Apo Al. One of the most common and easily available inbred strains of mice, C57/BL6, is the ideal model for our studies. We have already demonstrated in tissue culture that mouse fibroblasts transfected with an Apo Al expression vector produce HDL. We have also developed the capacity to produce lines of transgenic mice. We now propose to construct additional Apo Al expression vectors based on viral promoters and test these vectors in fibroblast and hepatoma cells. The viral promoter-Apo Al fusion genes will subsequently be used to produce lines of transgenic mice that express high levels of Apo Al. Mice that express high levels of HDL will be assayed for their resistance to atherosclerosis.
