In the past year, we have made several new transgenic mice lines. We recently made a reversible apoE KO mice using the Tet-Off system so that we can reversibly control the expression of apoE. In the absence of apoE, mice develop a profound dyslipidemia and atherosclerosis. We plan to use this model to examine the ability of several therapies to reverse atherosclerosis by restoring the expression of apoE while commencing the therapy. This should be a more relevant animal model compared to the commonly used atherosclerosis progression models for testing new cardiovascular therapies in reversing existing disease in humans. We also published 2 papers last year, describing a new transgenic animal models specifically expressing either ABCA1 or Arginase II in endothelial cells, using the Tie2 promoter. In the first model, we found that endothelial expression of ABCA1 only had a minor effect on circulating lipoprotein levels but was very effective in reducing the development of atherosclerosis. This study suggests an important role of ABCA1 in cholesterol efflux from endothelial cells. Arginase II overexpression in endothelial cells resulted in endothelial dysfunction and hypertension and markedly increased their propensity for atherosclerosis when on the apoE KO background. This study demonstrates the role of arginase II in depleting arginine levels for the production of NO and suggests that it may be a target for drug development.
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