Abstract 1026: Macrophage-specific Transgenic Expression of Human Macrophage Cholesterol Ester Hydrolase results in Significantly Reduced Atherosclerotic Lesions in LDLR-/- mice
Cholesterol ester hydrolase (CEH) catalyses the rate limiting step in free cholesterol efflux from macrophage foam cells and intracellular CEH levels negatively correlate with lipid accumulation in foam cells and susceptibility to atherosclerosis. In the present study we tested the hypothesis that macrophage-specific transgenic expression of human CEH will lead to reduced lesion development. Transgene construct where CEH expression is driven by scavenger receptor promoter/enhancer was used for the development of transgenic animals in C57BL/6 background. The founder (CEHTg) was crossed with LDLR-/- mice to generate LDLR-/-CEHTg animals. After confirming the maximum expression of human CEH in macrophages and enhanced free cholesterol efflux from macrophage foam cells from transgenic mice, control (LDLR-/-) and transgenic (LDLR-/-CEHTg) mice were fed a high-fat high-cholesterol diet for 16 weeks. Lesion development was assessed by en face analyses. Percent area of the aortic arch and the total aorta occupied by lesion was compared between males and females of control and transgenic mice and data are presented as Mean±sem for indicated number of animals . Transgenic expression of human macrophage CEH resulted in significant reduction in total as well as aortic arch lesions (p<0.05) in both male and female mice. In conclusion, transgenic expression of human macrophage CEH increased free cholesterol efflux from macrophage foam cells and significantly reduced diet-induced lesion formation in LDLR-/- mice. Further, CEH over-expression equally reduced lesion development in both genders. Thus, CEH may represent a potentially new target to attenuate atherosclerosis.