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Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.

dc.contributor.author Wu, Jiao-Hui
dc.contributor.author Zhang, Lisheng
dc.contributor.author Nepliouev, Igor
dc.contributor.author Brian, Leigh
dc.contributor.author Huang, Taiqin
dc.contributor.author Snow, Kamie P
dc.contributor.author Schickling, Brandon M
dc.contributor.author Hauser, Elizabeth R
dc.contributor.author Miller, Francis J
dc.contributor.author Freedman, Neil J
dc.contributor.author Stiber, Jonathan A
dc.date.accessioned 2021-07-01T16:22:15Z
dc.date.available 2021-07-01T16:22:15Z
dc.date.issued 2021-04-29
dc.identifier 6259142
dc.identifier.issn 0008-6363
dc.identifier.issn 1755-3245
dc.identifier.uri https://hdl.handle.net/10161/23419
dc.description.abstract <h4>Aims</h4>The F-actin-binding protein Drebrin inhibits smooth muscle cell (SMC) migration, proliferation and pro-inflammatory signaling. Therefore, we tested the hypothesis that Drebrin constrains atherosclerosis.<h4>Methods and results</h4>SM22-Cre+/Dbnflox/flox/Ldlr-/- (SMC-Dbn-/-/Ldlr-/-) and control mice (SM22-Cre+/Ldlr-/-, Dbnflox/flox/Ldlr-/-, and Ldlr-/-) were fed a Western diet for 14-20 weeks. Brachiocephalic arteries of SMC-Dbn-/-/Ldlr-/- mice exhibited 1.5- or 1.8-fold greater cross-sectional lesion area than control mice at 14 or 20 wk, respectively. Aortic atherosclerotic lesion surface area was 1.2-fold greater in SMC-Dbn-/-/Ldlr-/- mice. SMC-Dbn-/-/Ldlr-/- lesions comprised necrotic cores that were two-fold greater in size than those of control mice. Consistent with their bigger necrotic core size, lesions in SMC-Dbn-/- arteries also showed more transdifferentiation of SMCs to macrophage-like cells: 1.5- to 2.5-fold greater, assessed with BODIPY or with CD68, respectively. In vitro data were concordant: Dbn-/- SMCs had 1.7-fold higher levels of KLF4 and transdifferentiated to macrophage-like cells more readily than Dbnflox/flox SMCs upon cholesterol loading, as evidenced by greater up-regulation of CD68 and galectin-3. Adenovirally mediated Drebrin rescue produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs. During early atherogenesis, SMC-Dbn-/-/Ldlr-/- aortas demonstrated 1.6-fold higher levels of reactive oxygen species than control mouse aortas. The 1.8-fold higher levels of Nox1 in Dbn-/- SMCs was reduced to WT levels with KLF4 silencing. Inhibition of Nox1 chemically or with siRNA produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs.<h4>Conclusions</h4>We conclude that SMC Drebrin limits atherosclerosis by constraining SMC Nox1 activity and SMC transdifferentiation to macrophage-like cells.<h4>Translational perspective</h4>Drebrin is abundantly expressed in vascular smooth muscle cells (SMCs) and is up-regulated in human atherosclerosis. A hallmark of atherosclerosis is the accumulation of foam cells that secrete pro-inflammatory cytokines and contribute to plaque instability. A large proportion of these foam cells in humans derive from SMCs. We found that SMC Drebrin limits atherosclerosis by reducing SMC transdifferentiation to macrophage-like foam cells in a manner dependent on Nox1 and KLF4. For this reason, strategies aimed at augmenting SMC Drebrin expression in atherosclerotic plaques may limit atherosclerosis progression and enhance plaque stability by bridling SMC-to-foam-cell transdifferentiation.
dc.language eng
dc.publisher Oxford University Press (OUP)
dc.relation.ispartof Cardiovascular research
dc.relation.isversionof 10.1093/cvr/cvab156
dc.subject Drebrin
dc.subject NADPH oxidase
dc.subject Nox1
dc.subject VSMC
dc.subject atherosclerosis
dc.subject foam cell
dc.subject reactive oxygen species
dc.subject vascular smooth muscle cells
dc.title Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.
dc.type Journal article
duke.contributor.id Zhang, Lisheng|0219677
duke.contributor.id Schickling, Brandon M|0722989
duke.contributor.id Hauser, Elizabeth R|0203880
duke.contributor.id Miller, Francis J|0702828
duke.contributor.id Freedman, Neil J|0099413
duke.contributor.id Stiber, Jonathan A|0199105
dc.date.updated 2021-07-01T16:22:07Z
pubs.organisational-group School of Medicine
pubs.organisational-group Duke Molecular Physiology Institute
pubs.organisational-group Biostatistics & Bioinformatics
pubs.organisational-group Duke
pubs.organisational-group Institutes and Centers
pubs.organisational-group Basic Science Departments
pubs.organisational-group Medicine, Cardiology
pubs.organisational-group Medicine
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Staff
pubs.publication-status Published
duke.contributor.orcid Schickling, Brandon M|0000-0002-2312-268X
duke.contributor.orcid Hauser, Elizabeth R|0000-0003-0367-9189
duke.contributor.orcid Miller, Francis J|0000-0001-5822-0549


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