{"doi":"10.1093/cvr/cvab156","title":"Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation","abstract":"AIMS: The F-actin-binding protein Drebrin inhibits smooth muscle cell (SMC) migration, proliferation, and pro-inflammatory signalling. Therefore, we tested the hypothesis that Drebrin constrains atherosclerosis. METHODS AND RESULTS: 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 weeks, 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 were 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. CONCLUSION: We conclude that SMC Drebrin limits atherosclerosis by constraining SMC Nox1 activity and SMC transdifferentiation to macrophage-like cells.","journal":"Cardiovascular Research","year":2021,"id":170029,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9666,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":702005,"name":"Lisheng Zhang","orcid":"0000-0002-9276-6454","position":1,"is_corresponding":false},{"id":702840,"name":"Igor Nepliouev","orcid":null,"position":2,"is_corresponding":false},{"id":702841,"name":"Leigh Brian","orcid":null,"position":3,"is_corresponding":false},{"id":612649,"name":"Tai-Qin Huang","orcid":"0000-0002-6962-2292","position":4,"is_corresponding":false},{"id":702006,"name":"Kamie Snow","orcid":"0000-0003-1657-0908","position":5,"is_corresponding":false},{"id":702007,"name":"Brandon Schickling","orcid":"0000-0002-2312-268X","position":6,"is_corresponding":false},{"id":11396,"name":"Elizabeth R. Hauser","orcid":"0000-0003-0367-9189","position":7,"is_corresponding":false},{"id":16590,"name":"Francis J. Miller","orcid":"0000-0001-5822-0549","position":8,"is_corresponding":false},{"id":702008,"name":"Neil J. Freedman","orcid":"0000-0002-8593-8676","position":9,"is_corresponding":false},{"id":606679,"name":"Jonathan A. Stiber","orcid":"0000-0002-2301-585X","position":10,"is_corresponding":false},{"id":702839,"name":"Jiao‐Hui Wu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-18T23:46:19.728805Z","pmid":"33914863","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}