- 作者：Laura Calpe-Berdiel ; Ying Zhao ; Marjo de Graauw ; Dan Ye ; Peter J. van Santbrink ; A. Mieke Mommaas ; Am ; a Foks ; Martine Bot ; Illiana Meurs ; Johan Kuiper ; Jody T. Mack ; Mir ; a Van Eck ; Kenneth D. Tew ; Theo J.C. van Berkel
- 关键词：ABCA2 ; Macrophage ; Atherosclerosis ; Transplantation ; Cholesterol homeostasis
- 刊名：Atherosclerosis
- 出版年：2012
- 出版时间：August, 2012
- 年：2012
- 卷：223
- 期：2
- 页码：332-341
- 全文大小：1360 K
class=""h4"">Objective
The ABCA2 transporter shares high structural homology to ABCA1, which is crucial for the removal of excess cholesterol from macrophages and, by extension, in atherosclerosis. It has been suggested that ABCA2 sequesters cholesterol inside the lysosomes, however, little is known of the macrophage-specific role of ABCA2 in regulating lipid homeostasis in?vivo and in modulating susceptibility to atherosclerosis.class=""h4"">Methods
Chimeras with dysfunctional macrophage ABCA2 were generated by transplantation of bone marrow from ABCA2 knockout (KO) mice into irradiated LDL receptor (LDLr) KO mice.
class=""h4"">Results
Interestingly, lack of ABCA2 in macrophages resulted in a diminished lesion size in the aortic root (?24.5 % ) and descending thoracic aorta (?36.6 % ) associated with a 3-fold increase in apoptotic cells, as measured by both caspase 3 and TUNEL. Upon oxidized LDL exposure, macrophages from wildtype (WT) transplanted animals developed filipin-positive droplets in lysosomal-like compartments, corresponding to free cholesterol (FC) accumulation. In contrast, ABCA2-deficient macrophages displayed an abnormal diffuse distribution of FC over peripheral regions. The accumulation of neutral sterols in lipid droplets was increased in ABCA2-deficient macrophages, but primarily in cytoplasmic clusters and not in lysosomes. Importantly, apoptosis of oxLDL loaded macrophages lacking ABCA2 was increased 2.7-fold, probably as a consequence of the broad cellular distribution of FC.
class=""h4"">Conclusions
Lack of functional ABCA2 generates abnormalities in intracellular lipid distribution/trafficking in macrophages consistent with its lysosomal sequestering role, leading to an increased susceptibility to apoptosis in response to oxidized lipids and reduced atherosclerotic lesion development.