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Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.

Publication ,  Journal Article
Wu, J-H; Zhang, L; Nepliouev, I; Brian, L; Huang, T; Snow, KP; Schickling, BM; Hauser, ER; Miller, FJ; Freedman, NJ; Stiber, JA
Published in: Cardiovasc Res
February 21, 2022

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.

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Published In

Cardiovasc Res

DOI

EISSN

1755-3245

Publication Date

February 21, 2022

Volume

118

Issue

3

Start / End Page

772 / 784

Location

England

Related Subject Headings

  • Neuropeptides
  • NADPH Oxidase 1
  • Myocytes, Smooth Muscle
  • Muscle, Smooth, Vascular
  • Mice, Knockout
  • Mice
  • Cross-Sectional Studies
  • Cells, Cultured
  • Cell Transdifferentiation
  • Cardiovascular System & Hematology
 

Citation

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Wu, J.-H., Zhang, L., Nepliouev, I., Brian, L., Huang, T., Snow, K. P., … Stiber, J. A. (2022). Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation. Cardiovasc Res, 118(3), 772–784. https://doi.org/10.1093/cvr/cvab156
Wu, Jiao-Hui, Lisheng Zhang, Igor Nepliouev, Leigh Brian, Taiqin Huang, Kamie P. Snow, Brandon M. Schickling, et al. “Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.Cardiovasc Res 118, no. 3 (February 21, 2022): 772–84. https://doi.org/10.1093/cvr/cvab156.
Wu J-H, Zhang L, Nepliouev I, Brian L, Huang T, Snow KP, et al. Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation. Cardiovasc Res. 2022 Feb 21;118(3):772–84.
Wu, Jiao-Hui, et al. “Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.Cardiovasc Res, vol. 118, no. 3, Feb. 2022, pp. 772–84. Pubmed, doi:10.1093/cvr/cvab156.
Wu J-H, Zhang L, Nepliouev I, Brian L, Huang T, Snow KP, Schickling BM, Hauser ER, Miller FJ, Freedman NJ, Stiber JA. Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation. Cardiovasc Res. 2022 Feb 21;118(3):772–784.
Journal cover image

Published In

Cardiovasc Res

DOI

EISSN

1755-3245

Publication Date

February 21, 2022

Volume

118

Issue

3

Start / End Page

772 / 784

Location

England

Related Subject Headings

  • Neuropeptides
  • NADPH Oxidase 1
  • Myocytes, Smooth Muscle
  • Muscle, Smooth, Vascular
  • Mice, Knockout
  • Mice
  • Cross-Sectional Studies
  • Cells, Cultured
  • Cell Transdifferentiation
  • Cardiovascular System & Hematology