Targeting Filamin A Reduces Macrophage Activity and Atherosclerosis

Sashidar Bandaru, Chandu Ala, Reza Salimi, Murali K. Akula, Matias Ekstrand, Sravani Devarakonda, Joakim Karlsson, Jimmy Van Den Eynden, Göran Bergström, Erik Larsson, Max Levin, Jan Borén, Martin O. Bergo, Levent M. Akyürek

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)


Background: The actin-binding protein FLNA (filamin A) 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 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 AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). 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 intermediate human atherosclerotic plaques. Flnao/fl/LC macrophages proliferated and migrated less than controls; expressed lower levels of phosphorylated AKT and ERK1/2; exhibited reduced foam cell formation and lipid uptake; and excreted more lipids. The deficiency of Flna in macrophages markedly reduced the size of aortic atherosclerotic plaques in both Ldlr-/-BMT:Flnao/fl/LC and AdPCSK9-infected Flnao/fl/LC mice. Intima/media ratios and numbers of CD68-positive macrophages in atherosclerotic plaques were lower in Flna-deficient mice than in control mice. Moreover, we found that STAT3 interacts with a calpain-cleaved carboxyl-terminal fragment of FLNA. Inhibiting calpain-mediated FLNA cleavage with calpeptin in macrophages reduced nuclear levels of phosphorylated STAT3, interleukin 6 secretion, foam cell formation, and lipid uptake. Finally, calpeptin treatment reduced the size of atherosclerotic plaques in C57BL/6 mice infected with AdPCSK9. Conclusions: Genetic inactivation of Flna and chemical inhibition of calpain-dependent cleavage of FLNA impaired macrophage signaling and function, and reduced atherosclerosis in mice, suggesting that drugs targeting FLNA may be useful in the treatment of atherosclerosis.

Original languageEnglish
Pages (from-to)67-79
Number of pages13
Issue number1
Publication statusPublished - 2 Jul 2019
Externally publishedYes


Dive into the research topics of 'Targeting Filamin A Reduces Macrophage Activity and Atherosclerosis'. Together they form a unique fingerprint.

Cite this