{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:42:57Z","timestamp":1790775777830,"version":"4.1.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,7,2]]},"abstract":"\n Background:<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n We analyzed FLNA expression in human carotid atherosclerotic plaques by immunofluorescence. We also produced mice with\n Flna<\/jats:italic>\n -deficient macrophages by breeding conditional\n Flna<\/jats:italic>\n -knockout mice (\n Flna<\/jats:italic>\n \n o\/fl<\/jats:italic>\n <\/jats:sup>\n ) with mice expressing\n Cre<\/jats:italic>\n from the macrophage-specific lysosome M promoter (\n LC<\/jats:italic>\n ). Atherosclerosis in vivo was studied by transplanting bone marrow from male\n Flna<\/jats:italic>\n \n o\/fl<\/jats:italic>\n <\/jats:sup>\n \/\n LC<\/jats:italic>\n mice to atherogenic low-density lipoprotein receptor\u2013deficient (\n Ldlr<\/jats:italic>\n \u2013\/\u2013<\/jats:sup>\n ) mice; and by infecting\n Flna<\/jats:italic>\n \n o\/fl<\/jats:italic>\n <\/jats:sup>\n and\n Flna<\/jats:italic>\n \n o\/fl<\/jats:italic>\n <\/jats:sup>\n \/\n LC<\/jats:italic>\n 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.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n We found that macrophage FLNA expression was higher in advanced than in intermediate human atherosclerotic plaques.\n Flna<\/jats:italic>\n \n o\/fl<\/jats:italic>\n <\/jats:sup>\n \/\n LC<\/jats:italic>\n 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\n Flna<\/jats:italic>\n in macrophages markedly reduced the size of aortic atherosclerotic plaques in both\n Ldlr<\/jats:italic>\n \n \u2013\/\u2013BMT:\n Flnao\/fl\/LC<\/jats:italic>\n <\/jats:sup>\n and AdPCSK9-infected\n Flna<\/jats:italic>\n \n o\/fl<\/jats:italic>\n <\/jats:sup>\n \/\n LC<\/jats:italic>\n mice. Intima\/media ratios and numbers of CD68-positive macrophages in atherosclerotic plaques were lower in\n Flna<\/jats:italic>\n -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.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n Genetic inactivation of\n Flna<\/jats:italic>\n 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.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circulationaha.119.039697","type":"journal-article","created":{"date-parts":[[2019,4,24]],"date-time":"2019-04-24T09:02:35Z","timestamp":1556096555000},"page":"67-79","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":55,"title":["Targeting Filamin A Reduces Macrophage Activity and Atherosclerosis"],"prefix":"10.1161","volume":"140","author":[{"given":"Sashidar","family":"Bandaru","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine (S.B., C.A., R.S., S.D., J.V.d.E., E.L., L.M.A.), Sahlgrenska Academy, University of Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandu","family":"Ala","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine (S.B., C.A., R.S., S.D., J.V.d.E., E.L., L.M.A.), Sahlgrenska Academy, University of Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Salimi","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine (S.B., C.A., R.S., S.D., J.V.d.E., E.L., L.M.A.), Sahlgrenska Academy, University of Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murali K.","family":"Akula","sequence":"additional","affiliation":[{"name":"Sahlgrenska Cancer Center, Sahlgrenska Academy (M.K.A., J.K., M.O.B.), Sahlgrenska Academy, University of Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matias","family":"Ekstrand","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, Institute of Medicine (M.E., G.B., M.L., J.B.), Sahlgrenska Academy, University of Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sravani","family":"Devarakonda","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine (S.B., C.A., R.S., S.D., J.V.d.E., E.L., L.M.A.), Sahlgrenska Academy, University of Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joakim","family":"Karlsson","sequence":"additional","affiliation":[{"name":"Sahlgrenska Cancer Center, Sahlgrenska Academy (M.K.A., J.K., M.O.B.), Sahlgrenska Academy, University of Gothenburg, Sweden."},{"name":"Department of Surgery, Institute of Clinical Sciences (J.K.), Sahlgrenska Academy, University of Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy","family":"Van den Eynden","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine (S.B., C.A., R.S., S.D., J.V.d.E., E.L., L.M.A.), Sahlgrenska Academy, University of Gothenburg, Sweden."},{"name":"Department of Human Structure and Repair, Anatomy and Embryology Unit, Ghent University, Belgium (J.V.d.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6ran","family":"Bergstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, Institute of Medicine (M.E., G.B., M.L., J.B.), Sahlgrenska Academy, University of Gothenburg, Sweden."},{"name":"Region V\u00e4stra G\u00f6taland, Sahlgrenska University Hospital, Department of Clinical Physiology, G\u00f6teborg, Sweden (G.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Larsson","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine (S.B., C.A., R.S., S.D., J.V.d.E., E.L., L.M.A.), Sahlgrenska Academy, University of Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Levin","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, Institute of Medicine (M.E., G.B., M.L., J.B.), Sahlgrenska Academy, University of Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Bor\u00e9n","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine, Institute of Medicine (M.E., G.B., M.L., J.B.), Sahlgrenska Academy, University of Gothenburg, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin 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