| dc.description.abstract | Atherosclerosis is chronic inflammatory disease characterised by the
formation of an atheromatous plaque that diminish the blood vessel lumen. The
plaque can also rupture and block small vessels, leading to complications such
as strokes and heart attacks. This process is triggered by the presence of
oxidised LDL (oxLDL) in the tunica intima of blood vessels and the consequent
macrophage recruitment. In these sites, macrophages capture and accumulate
oxLDL in their cytoplasm, turning into foam cells. These cells produce proinflammatory cytokines that recruit more immune cells, stimulating the
inflammatory process progression and plaque growth. Many studies try to
elucidate the role of oxLDL accumulation in macrophage activation and foam cell
formation. However, little is known about the biomechanical effects induced by
oxLDL in macrophages, as well as their consequences for cell activation that are
not directly related to the cholesterol accumulation in the cytoplasm of these
cells. In non-professional phagocytic cells, oxLDL induces increased membrane
rigidity and actin cytoskeleton alteration. These effects are partially reproducible
by cholesterol depletion and membrane rafts disorganization, induced by the
treatment with MβCD. Since membrane rafts are important domains to the
recruitment, organization and activity of plasma membrane proteins, alterations
in raft dynamics can lead to several effects in the cell. It was shown in nonprofessional phagocytic cells that raft disruption affects actin reorganization and
integrin distribution in the cell surface, also affecting cell migration and
membrane rigidity. However, little is known about the morphofunctional effects of
raft disruption in professional phagocytic cells, such as macrophages. Therefore,
the goal of this study is to analyse the morphological, mechanical and functional
effects of oxLDL treatment that are consequences of raft disruption, in
macrophages, in order to elucidate the contribution of rafts for the pathologic
process of atherosclerosis. We observed that the treatment with oxLDL alteres
raft conformation of bone marrow derived macrophages (BMDM). A similar effect
was observed in the treatment with MβCD. The similarities between the
treatments could also be observed in the actin cytoskeleton organization, cell
morphology and integrin distribution. OxLDL-treated macrophages showed
higher actin polimerization, diffuse integrin distribution and cell shrinkage similarly
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with the observed in MβCD-treated macrophages. Both treatments also
increased the physical interaction between the actin cytoskeleton and membrane
rafts, indicating a similar action mechanism. The physical alterations induced by
oxLDL and MβCD also lead to deficient migration in macrophages. These results
indicate that oxLDL can induce physical alterations in macrophages due to raft
desorganization. Those alterations can have implications in the macrophage
retention in the atheromatous plaque, the formation of foam cells, and
consequently, atherosclerosis progression. | |
