Targeting filamin A reduces macrophage activity and atherosclerosis
- Author
- Sashidar Bandaru, Chandu Ala, Reza Salimi, Murali K Akula, Matias Ekstrand, Sravani Devarakonda, Joakim Karlsson, Jimmy Van den Eynden (UGent) , Goran Bergström, Erik Larsson, Max Levin, Jan Borén, Martin O Bergo and Levent M Akyürek
- Organization
- 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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Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8613153
- 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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