Chronic Unpredictable Mild Stress Promotes Atherosclerosis via HMGB1/TLR4-Mediated Downregulation of PPARγ/LXRα/ABCA1 in ApoE-/- Mice.

Hong-Feng Gu,Zhao-Qian Xu,Ru-Meng Chen,Hui Li,Duan-Fang Liao,Ya-Ling Tang,Rong-Jie Zhang,Xi-Long Zheng,Lu Hu,Na Li

doi:10.3389/fphys.2019.00165

Abstract

Background: Although our previous studies have confirmed that the activation of TLR4 is implicated in the development of atherosclerosis induced by chronic unpredicted mild stress (CUMS), the underling mechanism is largely unclear. Here, we hypothesized that CUMS accelerates atherosclerotic development through lowering PPARγ/LXRα-ABCA1 expression via HMGB1/TLR4 signaling.Methods: In present study, CUMS atherosclerotic animal models were established with AopE-/- mice, and CUMS Raw 264.7 macrophage models were mimicked by high corticosterone treatment, These models were treated with Ethyl pyruvate (EP, an inhibitor of HMGB1), TLR4 inhibitor TAK-242, and PPARγ agonist RSG (Rosiglitazone) to test our hypothesis, respectively.Results: Our results indicated that the protein levels of HMGB1, TLR4, and pro-inflammatory cytokines including IL-1β, TNF-α were elevated with the development of atherosclerosis in CUMS mice, while the expressions of PPARγ, LXRα, and ABCA1 declined. Notably, HMGB1 inhibition by EP reversed CUMS-induced atherosclerotic development, pro-inflammatory cytokines upregulation, and PPARγ/LXRα-ABCA1 downregulation. The same trend was observed in the stressed mice treatment with TAK-242. Further experimental evidences indicated that EP, TAK-242, and RSG treatment notably corrected foam cell formation, HMGB1 release, and down-regulation of LXRα and ABCA1 in CUMS Raw 264.7 macrophage model.Conclusion: These results indicate that CUMS exacerbates atherosclerosis is likely via HMGB1-mediated downregulation of PPARγ/LXRα-ABCA1 through TLR4. These data reveal a novel mechanism by which CUMS aggravates atherosclerosis and may offer a potential therapeutic target for this disease.

Highlights

Accumulating evidence indicates that chronic stress, especially chronic psychological stress, is a critical risk factor for atherosclerotic diseases (Kaplan et al, 1983; Rozanski et al, 1999; Empana et al, 2005; Bagheri et al, 2016)
To determine whether chronic unpredictable mild stress (CUMS) could increase the release of High-mobility group box 1 (HMGB1), its protein concentrations in serum were measured by Enzyme-linked immunosorbent assay (ELISA) assay
HMGB1/Toll-like receptor 4 (TLR4) signaling on the development of atherosclerosis induced by CUMS

Summary

Introduction

Accumulating evidence indicates that chronic stress, especially chronic psychological stress, is a critical risk factor for atherosclerotic diseases (Kaplan et al, 1983; Rozanski et al, 1999; Empana et al, 2005; Bagheri et al, 2016). Substantial studies confirm that inflammation plays a critical role in atherogenesis induced by chronic stress (Empana et al, 2005; Ranjit et al, 2007; Wirtz and von Kanel, 2017), the precise mechanisms underlying this atherosclerosis-related inflammation elicited by stress remain largely unknown. Our previous studies revealed that TLR4-mediated inflammation is involved in the progression of atherogenesis induced by chronic unpredictable mild stress (CUMS) (Gu et al, 2009; Tang et al, 2015). The underlying mechanism atherosclerosis-related inflammation elicited by TLR4 activation in the context of this chronic stress is still unclear. Our previous studies have confirmed that the activation of TLR4 is implicated in the development of atherosclerosis induced by chronic unpredicted mild stress (CUMS), the underling mechanism is largely unclear. We hypothesized that CUMS accelerates atherosclerotic development through lowering PPARγ/LXRα-ABCA1 expression via HMGB1/TLR4 signaling

Methods

Results

Discussion

Conclusion