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.date.updated | 2021-07-01T16:22:07Z | |
| dc.description.abstract | AimsThe 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.Methods and resultsSM22-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.ConclusionsWe conclude that SMC Drebrin limits atherosclerosis by constraining SMC Nox1 activity and SMC transdifferentiation to macrophage-like cells.Translational perspectiveDrebrin 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.identifier | 6259142 | |
| dc.identifier.issn | 0008-6363 | |
| dc.identifier.issn | 1755-3245 | |
| dc.identifier.uri | ||
| 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.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 | |
| duke.contributor.orcid | Freedman, Neil J|0000-0002-8593-8676 | |
| duke.contributor.orcid | Stiber, Jonathan A|0000-0002-2301-585X | |
| 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 |
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