Targeting Filamin A Reduces Macrophage Activity and Atherosclerosis

Background: The actin-binding protein filamin A (FLNA) regulates signal transduction important for cell locomotion, but the role of macrophage-specific FLNA during atherogenesis has not been explored. Methods: We analyzed FLNA expression in human carotid atherosclerotic plaques by immunofluorescence. We also produced mice with Flna-deficient macrophages by breeding conditional Flna-knockout mice (Flnao/fl) with mice expressing Cre from the macrophage-specific lysosome M promoter (LC). Atherosclerosis in vivo was studied by transplanting bone-marrow (BMT) from male Flnao/fl/LC mice to atherogenic low-density lipoprotein receptor-deficient (Ldlr-/-) mice; and by infecting Flnao/fl and Flnao/fl/LC mice with an adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9 (AdPCSK9). Furthermore, C57BL/6 mice were infected with AdPCSK9 and then treated with the calpain inhibitor calpeptin to inhibit FLNA cleavage. Results: We found that macrophage FLNA expression was higher in advanced than in...