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

• Type of Material: Article
• Authors: Jinoh Kim, Ewha Womans University; Jung-Yeon Yoo, Ewha Womans University; Jung Min Suh, Ewha Womans University; Sujin Park, Ewha Womans University; Dongmin Kang, Ewha Womans University; Hanjoong Jo, Emory University; Yun Soo Bae, Ewha Womans University
• Language: English
• Date: 2019-07-10
• Publisher: Springer Nature [academic journals on nature.com]: Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s12276-019-0275-6
• Title of Journal or Parent Work: Experimental and Molecular Medicine
• ISSN: 1226-3613
• Volume: 51
• Issue: 7
• Start Page: 78
• End Page: 78
• Grant/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).
• Keywords: TOLL-LIKE RECEPTORS; INFLAMMATION; Science & Technology; IL-6 EXPRESSION; Biochemistry & Molecular Biology; PATHOPHYSIOLOGY; PROTEIN; Medicine, Research & Experimental; Life Sciences & Biomedicine; OXIDASE-4; Research & Experimental Medicine; TLR4; INTERLEUKIN-6; ACTIVATION
• Research Categories: Chemistry, Biochemistry; Biology, Physiology

Abstract

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.