Lack of RAC1 in macrophages protects against atherosclerosis
Lack of RAC1 in macrophages protects against atherosclerosis
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DOI：
10.1371/journal.pone.0239284
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发表时间：
2020-09-17
期刊：
影响因子：
3.7
通讯作者：
Akyurek, Levent M.
中科院分区：
文献类型：
--
作者：
Bandaru, Sashidar;Ala, Chandu;Akyurek, Levent M.
The Rho GTPase RAC1 is an important regulator of cytoskeletal dynamics, but the role of macrophage-specific RAC1 has not been explored during atherogenesis. We analyzed RAC1 expression in human carotid atherosclerotic plaques using immunofluorescence and found higher macrophage RAC1 expression in advanced plaques compared with intermediate human atherosclerotic plaques. We then produced mice withRac1-deficient macrophages by breeding conditional floxedRac1mice (Rac1(fl/fl)) with mice expressing Cre from the macrophage-specific lysosome M promoter (LC). Atherosclerosis was studiedin vivoby infectingRac1(fl/fl)andRac1(fl/fl)/LCmice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9).Rac1(fl/fl)/LC macrophages secreted lower levels of IL-6 and TNF-alpha and exhibited reduced foam cell formation and lipid uptake. The deficiency ofRac1in macrophages reduced the size of aortic atherosclerotic plaques in AdPCSK9-infectedRac1(fl/fl)/LCmice. Compare with controls, intima/media ratios, the size of necrotic cores, and numbers of CD68-positive macrophages in atherosclerotic plaques were reduced inRac1-deficient mice. Moreover, we found that RAC1 interacts with actin-binding filamin A. Macrophages expressed increased RAC1 levels in advanced human atherosclerosis. Genetic inactivation of RAC1 impaired macrophage function and reduced atherosclerosis in mice, suggesting that drugs targeting RAC1 may be useful in the treatment of atherosclerosis.
