Open AccessLack of RAC1 in macrophages protects against atherosclerosis
Author(s) -
Sashidar Bandaru,
Chandu Ala,
Matias Ekstrand,
Murali K. Akula,
Matteo Pedrelli,
Xi Liu,
Göran Bergström,
Liliana Håversen,
Jan Borén,
Martin O. Bergö,
Levent M. Akyürek
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0239284
Subject(s) - kexin , rac1 , filamin , macrophage , proprotein convertase , foam cell , cd68 , biology , microbiology and biotechnology , chemistry , immunology , cell , cytoskeleton , lipoprotein , endocrinology , in vitro , cholesterol , biochemistry , signal transduction , immunohistochemistry , ldl receptor
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 with Rac1 -deficient macrophages by breeding conditional floxed Rac1 mice ( Rac1 fl/fl ) with mice expressing Cre from the macrophage-specific lysosome M promoter ( LC ). Atherosclerosis was studied in vivo by infecting Rac1 fl/fl and Rac1 fl/fl / LC mice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). Rac1 fl/fl /LC macrophages secreted lower levels of IL-6 and TNF-α and exhibited reduced foam cell formation and lipid uptake. The deficiency of Rac1 in macrophages reduced the size of aortic atherosclerotic plaques in AdPCSK9-infected Rac1 fl/fl / LC mice. Compare with controls, intima/media ratios, the size of necrotic cores, and numbers of CD68-positive macrophages in atherosclerotic plaques were reduced in Rac1 -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.