Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation

Jiao-Hui Wu; Lisheng Zhang; Igor Nepliouev; Leigh Brian; Taiqin Huang; Kamie P Snow; Brandon M Schickling; Elizabeth R Hauser; Francis J Miller; Neil J Freedman; Jonathan A Stiber

doi:10.1093/cvr/cvab156

Back

Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation

Journal article

Peer reviewed

Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation

Jiao-Hui Wu, Lisheng Zhang, Igor Nepliouev, Leigh Brian, Taiqin Huang, Kamie P Snow, Brandon M Schickling, Elizabeth R Hauser, Francis J Miller, Neil J Freedman, …

Cardiovascular research, Vol.118(3), pp.772-784

02/21/2022

DOI: 10.1093/cvr/cvab156

PMCID: PMC8859638

PMID: 33914863

Files and links (1)

url

https://www.ncbi.nlm.nih.gov/pmc/articles/8859638View

Open Access

Abstract

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. 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. We conclude that SMC Drebrin limits atherosclerosis by constraining SMC Nox1 activity and SMC transdifferentiation to macrophage-like cells.

Animals

Atherosclerosis - genetics

Atherosclerosis - prevention & control

Cell Transdifferentiation

Cells, Cultured

Cross-Sectional Studies

Mice

Mice, Knockout

Muscle, Smooth, Vascular - cytology

Myocytes, Smooth Muscle - cytology

Myocytes, Smooth Muscle - metabolism

NADPH Oxidase 1 - genetics

Neuropeptides - genetics

Details

Title: Subtitle: Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation
Creators: Jiao-Hui Wu - Department of Medicine (Cardiology), Duke University Medical Center, 10 Duke Medicine Circle, Durham, NC 27710, USA
Lisheng Zhang - Department of Medicine (Cardiology), Duke University Medical Center, 10 Duke Medicine Circle, Durham, NC 27710, USA
Igor Nepliouev - Department of Medicine (Cardiology), Duke University Medical Center, 10 Duke Medicine Circle, Durham, NC 27710, USA
Leigh Brian - Department of Medicine (Cardiology), Duke University Medical Center, 10 Duke Medicine Circle, Durham, NC 27710, USA
Taiqin Huang - Department of Medicine (Cardiology), Duke University Medical Center, 10 Duke Medicine Circle, Durham, NC 27710, USA
Kamie P Snow - Department of Medicine (Cardiology), Duke University Medical Center, 10 Duke Medicine Circle, Durham, NC 27710, USA
Brandon M Schickling - Duke Medical Center
Elizabeth R Hauser - Duke University School of Medicine
Francis J Miller - Atrium Health Wake Forest Baptist
Neil J Freedman - Department of Medicine (Cardiology), Duke University Medical Center, 10 Duke Medicine Circle, Durham, NC 27710, USA
Jonathan A Stiber - Duke Medical Center
Resource Type: Journal article
Publication Details: Cardiovascular research, Vol.118(3), pp.772-784
DOI: 10.1093/cvr/cvab156
PMID: 33914863
PMCID: PMC8859638
NLM abbreviation: Cardiovasc Res
ISSN: 0008-6363
eISSN: 1755-3245
Grant note: R01 HL121531 / NHLBI NIH HHS T32 HL007101 / NHLBI NIH HHS R01 HL147157 / NHLBI NIH HHS
Language: English
Date published: 02/21/2022
Academic Unit: Obstetrics and Gynecology
Record Identifier: 9984966746702771

Metrics

1 Record Views