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Targeting filamin A reduces macrophage activity and atherosclerosis

(2019) CIRCULATION. 140(1). p.67-79
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Abstract
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 (Flna(o/fl)) with mice expressing Cre from the macrophage-specific lysosome M promoter (LC). Atherosclerosis in vivo was studied by transplanting bone marrow from male Flna(o/fl)/LC mice to atherogenic low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice; and by infecting Flna(o/fl) and Flna(o/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. Flna(o/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 Flna(o/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.
Keywords
cytoskeleton, endarterectomy, lipids, models, animal, LOW-DENSITY-LIPOPROTEIN, ACTIN CYTOSKELETON, CALPAIN, DEFICIENCY, MIGRATION, MICE, CELL, INTERLEUKIN-6, INHIBITION, MECHANISMS

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MLA
Bandaru, Sashidar, et al. “Targeting Filamin A Reduces Macrophage Activity and Atherosclerosis.” CIRCULATION, vol. 140, no. 1, 2019, pp. 67–79, doi:10.1161/circulationaha.119.039697.
APA
Bandaru, S., Ala, C., Salimi, R., Akula, M. K., Ekstrand, M., Devarakonda, S., … Akyürek, L. M. (2019). Targeting filamin A reduces macrophage activity and atherosclerosis. CIRCULATION, 140(1), 67–79. https://doi.org/10.1161/circulationaha.119.039697
Chicago author-date
Bandaru, Sashidar, Chandu Ala, Reza Salimi, Murali K Akula, Matias Ekstrand, Sravani Devarakonda, Joakim Karlsson, et al. 2019. “Targeting Filamin A Reduces Macrophage Activity and Atherosclerosis.” CIRCULATION 140 (1): 67–79. https://doi.org/10.1161/circulationaha.119.039697.
Chicago author-date (all authors)
Bandaru, Sashidar, Chandu Ala, Reza Salimi, Murali K Akula, Matias Ekstrand, Sravani Devarakonda, Joakim Karlsson, Jimmy Van den Eynden, Goran Bergström, Erik Larsson, Max Levin, Jan Borén, Martin O Bergo, and Levent M Akyürek. 2019. “Targeting Filamin A Reduces Macrophage Activity and Atherosclerosis.” CIRCULATION 140 (1): 67–79. doi:10.1161/circulationaha.119.039697.
Vancouver
1.
Bandaru S, Ala C, Salimi R, Akula MK, Ekstrand M, Devarakonda S, et al. Targeting filamin A reduces macrophage activity and atherosclerosis. CIRCULATION. 2019;140(1):67–79.
IEEE
[1]
S. Bandaru et al., “Targeting filamin A reduces macrophage activity and atherosclerosis,” CIRCULATION, vol. 140, no. 1, pp. 67–79, 2019.
@article{8613153,
  abstract     = {{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 (Flna(o/fl)) with mice expressing Cre from the macrophage-specific lysosome M promoter (LC). Atherosclerosis in vivo was studied by transplanting bone marrow from male Flna(o/fl)/LC mice to atherogenic low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice; and by infecting Flna(o/fl) and Flna(o/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. Flna(o/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 Flna(o/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.}},
  author       = {{Bandaru, Sashidar and Ala, Chandu and Salimi, Reza and Akula, Murali K and Ekstrand, Matias and Devarakonda, Sravani and Karlsson, Joakim and Van den Eynden, Jimmy and Bergström, Goran and Larsson, Erik and Levin, Max and Borén, Jan and Bergo, Martin O and Akyürek, Levent M}},
  issn         = {{0009-7322}},
  journal      = {{CIRCULATION}},
  keywords     = {{cytoskeleton,endarterectomy,lipids,models,animal,LOW-DENSITY-LIPOPROTEIN,ACTIN CYTOSKELETON,CALPAIN,DEFICIENCY,MIGRATION,MICE,CELL,INTERLEUKIN-6,INHIBITION,MECHANISMS}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{67--79}},
  title        = {{Targeting filamin A reduces macrophage activity and atherosclerosis}},
  url          = {{http://doi.org/10.1161/circulationaha.119.039697}},
  volume       = {{140}},
  year         = {{2019}},
}

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