Impaired development of atherosclerosis in Abcg1-/- Apoe-/- mice: identification of specific oxysterols that both accumulate in Abcg1-/- Apoe-/- tissues and induce apoptosis.

摘要

OBJECTIVE: To generate Abcg1(-/-) Apoe(-/-) mice to understand the mechanism and cell types involved in changes in atherosclerosis after loss of ABCG1. METHODS AND RESULTS: ABCG1 is highly expressed in macrophages and endothelial cells, 2 cell types that play important roles in the development of atherosclerosis. Abcg1(-/-) Apoe(-/-) and Apoe(-/-) mice and recipient Apoe(-/-) mice that had undergone transplantation with bone marrow from Apoe(-/-) or Abcg1(-/-) Apoe(-/-) mice were fed a Western diet for 12 or 16 weeks before quantification of atherosclerotic lesions. These studies demonstrated that loss of ABCG1 from all tissues, or from only hematopoietic cells, was associated with significantly smaller lesions that contained increased numbers of TUNEL- and cleaved caspase 3-positive apoptotic Abcg1(-/-) macrophages. We also identified specific oxysterols that accumulate in the brains and macrophages of the Abcg1(-/-) Apoe(-/-) mice. These oxysterols promoted apoptosis and altered the expression of proapoptotic genes when added to macrophages in vitro. CONCLUSIONS: Loss of ABCG1 from all tissues or from only hematopoietic cells results in smaller atherosclerotic lesions populated with increased apoptotic macrophages, by processes independent of ApoE. Specific oxysterols identified in tissues of Abcg1(-/-) Apoe(-/-) mice may be critical because they induce macrophage apoptosis and the expression of proapoptotic genes.