Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 Pathway.

Zhongli Chen,Yanpin Wang,Lijuan Cao,Ke Yang,Yan Liu,Xiaojie Zhang,Fan Xiao,Ying Yang,Melvin R Hayden,Yuanyuan Chen,Qiqi Xue

doi:10.1155/2021/6639252

Abstract

Oxidized low-density lipoprotein (oxLDL) induced a foam-cell-like phenotype of the vascular smooth muscle cells (VSMCs), leading to the inflammatory responses incorporating Toll-like receptor- (Tlr-) mediated cellular alterations. However, the role of Tlr4 in foam cell formation and underlying molecular pathways has not been comprehensively elucidated. To further investigate the mechanism, VSMCs were incubated with different doses of oxLDL, and then, the lipid, reactive oxygen species (ROS) accumulation, Tlr family genes, and the foam cell phenotype were explored. We observed that oxLDL induced foam cell-like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. Furthermore, in the Tlr family, Tlr4 demonstrated the strongest upregulation under oxLDL stimulation. Simultaneously, oxLDL induced activation of Src, higher expression of Nox2, and lower expression of Mnsod, Sirt1, and Sirt3. By interfering the TLR4 expression, the phenotype alteration, lipid accumulation in VSMCs, and Src kinase activation induced by oxLDL were abolished. After interfering Src activation, the oxLDL-induced lipid accumulation and foam cell phenotype in VSMCs were also alleviated. Furthermore, the ROS accumulation, upregulated Nox2 expression, downregulated Sirt1, Sirt3, and Mnsod expression in VSMCs under oxLDL stimulation were also relieved after the knockdown of Tlr4. Additionally, overexpression of Sirt1 and Sirt3 ameliorated the ROS accumulation and foam cell-like marker expression in VSMCs. These results demonstrated that beyond its familiar role in regulating inflammation response, Tlr4 is a critical regulator in oxLDL-induced foam cell formation in VSMCs via regulating Src kinase activation as well as Sirt1 and Sirt3 expression.

Highlights

Coronary artery disease (CAD) is a leading health burden contributing to high morbidity and mortality worldwide [1]
We demonstrated that oxidized low-density lipoprotein (oxLDL) induced the transition of vascular smooth muscle cells (VSMCs) to foam cells by promoting lipid accumulation and reactive oxygen species (ROS) production via raising the expression of a key linking molecule-Tlr4
OxLDL-induced lipid and ROS accumulation and phenotype alteration in VSMCs were at least partly attributed to Tlr4-regulated Src activation and Sirt1 and Sirt3 upregulation

Summary

Introduction

Coronary artery disease (CAD) is a leading health burden contributing to high morbidity and mortality worldwide [1]. During the process of atherosclerosis, mounting foam cell formation and necrosis invoked the inflammation storm, Mediators of Inflammation which aggravated instability of plaque and led to acute myocardial infarction [3, 4]. The VSMC underwent phenotype transition from the classical contractile state to the macrophage-like phenotype [8]. Such VSMC-derived foam cells accelerated the progression of atherosclerosis [9, 10]. Though a few scavenger receptors participated in lipid uptake during foam cell formation, the specific mechanism contributing to lipid accumulation in VSMCs was still unclear. To acquire a better understanding of VSMC alteration in atherosclerosis, it is necessary to clarify the mechanism underlying the lipid accumulation in VSMCs

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Conclusion