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Targeting filamin A reduces macrophage activity and atherosclerosis.

Artikel i vetenskaplig tidskrift
Författare Sashidar Bandaru
Chandu Ala
Reza Salimi
Murali K Akula
Matias Ekstrand
Sravani Devarakonda
Joakim Karlsson
Jimmy Van den Eynden
Göran M L Bergström
Max Levin
Jan Borén
Martin O. Bergo
Levent Akyürek
Publicerad i Circulation
Volym 140
Nummer/häfte 1
Sidor 67-79
ISSN 1524-4539
Publiceringsår 2019
Publicerad vid Wallenberglaboratoriet
Institutionen för kliniska vetenskaper, Avdelningen för onkologi
Institutionen för biomedicin, avdelningen för patologi
Sahlgrenska Cancer Center
Institutionen för medicin
Center for Cardiovascular and Metabolic Research (CMR)
Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
Institutionen för medicin, avdelningen för molekylär och klinisk medicin
Sidor 67-79
Språk en
Länkar dx.doi.org/10.1161/CIRCULATIONAHA.1...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Molekylär medicin (genetik och patologi), Kardiovaskulär medicin

Sammanfattning

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.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.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.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.

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