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

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.

The role of NOX4 in pulmonary diseases

“…Most NOX proteins generate O 2 − , but NOX4 catalyzes the reduction of molecular oxygen to H 2 O 2 . This feature gives NOX4 some specific roles in different cellular functions, such as proliferation (Petry et al, 2006), differentiation (Clempus et al, 2007), migration (J. Kim et al, 2019; Lyle et al, 2009; Meng et al, 2015; M. Zhang, Xu, Qiu, & Jiang, 2019), apoptosis (Pedruzzi et al, 2004), senescence (Canugovi et al, 2019), matrix secretion (Hecker et al, 2009), and angiogenesis (A. Z. Chen, Li, Zhou, & Min, 2017).…”

Nox4-IGF2 Axis Promotes Differentiation of Embryoid Body Cells Into Derivatives of the Three Embryonic Germ Layers

“…The exact signaling events that lead to transcriptional activation of IGF and TGF-β1 should be further examined. It is established that Nox4 activates NF-κB and that NF-κB activates TGF-β genes [ 32 – 35 ]. It has also been reported that Nox signaling leads to activation of Smad pathway [ 33 ].…”

Quantitative Proteomics Reveal the Protective Effects of the Combined Chinese Herbal Extracts Against Alzheimer's Disease via Modulating the Expression of Synapse-associated Proteins in Mouse Model

“…Numerous studies have demonstrated that activated P38MAPK has been found in human AD brain tissue, furthermore, recent studies have corroborated the fact that there is an interaction between phospho-PKA and phospho-P38MAPK expression. In most systems, MAPK stimulates the transcriptional activity of NF-kB, while PKA suppresses it [33]. In addition, PKA activator-SKF38393 was in fact developed as potential therapeutics for AD with purpose to block P38MAPK phosphorylation [34].…”