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Filamin A in Cardiovascular Remodeling

Författare Sashidar Bandaru
Datum för examination 2018-11-29
ISBN 978-91-7833-230-4
Publiceringsår 2018
Publicerad vid Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
Språk en
Länkar https://gupea.ub.gu.se/handle/2077/...
Ämnesord Filamin A, Cardiovascular remodelling
Ämneskategorier Kardiologi


Filamin A (FLNA) is a large actin-binding cytoskeletal protein that stabilizes actin networks and integrates them with cell membranes. FLNA is therefore important for cell motility and organ development. We recently discovered that a C-terminal fragment of FLNA (FLNACT) can be cleaved off by calpain and stimulate angiogenesis by transporting transcription factors into the nucleus. However, little is known about the role of FLNA in cell types that participate in the pathogenesis of vascular diseases where angiogenesis typically plays an important role. In this thesis, we defined the impact of inactivating Flna in mouse vascular endothelial cells and macrophages on the pathogenesis of myocardial infarction (MI) and atherosclerosis, respectively—and made several exciting discoveries. In Study I, we induced MI by ligating the left descending coronary artery in wt control mice and mice lacking FLNA in endothelial cells. The Flna-knockout mice developed larger MI lesions than controls, and exhibited larger and thinner left ventricles, impaired cardiac function, elevated plasma levels of the cardiac damage biomarker NT-proBNP, and reduced plasma levels of the angiogenesis-promoting factor VEGF-A. Hearts from the Flna-knockout mice exhibited reduced capillary structures within infarcted regions; and cultured Flna-deficient endothelial cells showed impaired migration and tubular formation, along with reduced levels of the signaling molecules p-ERK and p-AKT and the small GTPase RAC1. In Study II, we first discovered that FLNA expression was higher in human carotid arteries with advanced atherosclerotic plaques than with intermediate plaques. We generated mice lacking FLNA in macrophages and found that their macrophages proliferated and migrated less compared with littermate controls. Moreover, Flna-deficient macrophages exhibited reduced levels of p-ERK and p-AKT, and reduced lipid uptake and increased cholesterol efflux. In two different mouse atherosclerosis models, the knockout of FLNA in macrophages markedly reduced lesion size and number of CD68-positive lesional macrophages. Interestingly, the calpain-cleaved FLNACT fragment interacted strongly with STAT3 in wt macrophages. Inhibiting FLNA cleavage with the calpain inhibitor calpeptin reduced nuclear p-STAT3 levels and subsequent IL-6 secretion in vitro; and reduced atherosclerotic lesions in vivo. We conclude that FLNA interacts with transcription factors and thereby regulates angiogenesis and inflammatory responses which are important events in the progression of MI and atherosclerosis. These findings identify FLNA as an important new mediator of cardiovascular remodeling and as a potential target for therapy.

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