The flagellin-TLR5-Nox4 axis promotes the migration of smooth muscle cells in atherosclerosis

Jinoh Kim, Jung Yeon Yoo, Jung Min Suh, Sujin Park, Dongmin Kang, Hanjoong Jo, Yun Soo Bae

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


We hypothesized that NADPH oxidase 4 (Nox4) is involved in the formation of neointimal atherosclerotic plaques through the migration of smooth muscle cells (SMCs) in response to flagellin. Here, we demonstrate that TLR5-mediated Nox4 activation regulates the migration of SMCs, leading to neointimal plaque formation in atherosclerosis. To investigate the molecular mechanism by which the TLR5-Nox4 cascade mediates SMC migration, we analyzed the signaling cascade in primary vascular SMCs (VSMCs) from wild-type (WT) or Nox4 KO mice. Stimulation of VSMCs from Nox4 KO mice with flagellin failed to induce H2O2 production and Rac activation compared with stimulation of VSMCs from WT mice. Moreover, the migration of Nox4-deficient VSMCs was attenuated in response to flagellin in transwell migration and wound healing assays. Finally, we performed partial carotid artery ligation in ApoE KO and Nox4ApoE DKO mice fed a high-fat diet (HFD) with or without recombinant FliC (rFliC) injection. Injection of rFliC into ApoE KO mice fed a HFD resulted in significantly increased SMC migration into the intimal layer, whereas SMC accumulation was not detected in Nox4ApoE DKO mice. We conclude that activation of the TLR5-Nox4 cascade plays an important role in the formation of neointimal atherosclerotic plaques.

Original languageEnglish
Article number78
JournalExperimental and Molecular Medicine
Issue number7
StatePublished - 1 Jul 2019

Bibliographical note

Funding Information:
This work was supported by a National Research Foundation of Korea (NRF) grant (No. 2012R1A5A1048236 to YSB), by the Aging Project (2017M3A9D8062955 to YSB), by a stem cell grant (2017M3A9B3061850 to YSB) funded by the Ministry of Science and ICT, and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI, grant number HI15C2800).

Publisher Copyright:
© 2019, The Author(s).


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