Corilagin Ameliorates Atherosclerosis in Peripheral Artery Disease via the Toll-Like Receptor-4 Signaling Pathway in vitro and in vivo.

Yujie Wang,Yiping Dang,Yunfei Chen,Zhilin Chen,Yiqing Li,Pan Liu,Peng Song,Yao Wang,Shaojun Zhang,Lei Luo,Yingying Luo,Lei Zhao

doi:10.3389/fimmu.2020.01611

Abstract

We investigated if corilagin can ameliorate or reverse atherosclerotic development via the toll-like receptor 4 (TLR4) signaling pathway in vitro and in vivo. Ana-1 cells or mouse peritoneal macrophages (MPMs) were stimulated with oxidized low-density lipoprotein followed by corilagin treatment. TLR4 expression in Ana-1 cells was upregulated by lentiviral transduction and downregulated by small interfering RNA. Peripheral blood mononuclear cells (PBMCs), plasma samples, and femoral arteries were collected from rats exhibiting peripheral artery disease (PAD). mRNA and protein expression of TLR4 and downstream molecules were decreased significantly by corilagin treatment in Ana-1 cells, MPMs, and rat PBMCs, and the reduction remained irrespective of downregulation or upregulation of TLR4 expression in Ana-1 cells. Corilagin also exerted a prominent effect on changes in plasma levels of cytokines and the pathologic manifestation of atherosclerosis in femoral arteries. Corilagin could ameliorate the development of atherosclerotic plaques by inhibiting the TLR4 signaling pathway in monocyte/macrophages and reduce the release of proinflammatory cytokines. This study provides a new therapeutic target and new niche targeting drug to oppose atherosclerosis and reveals the enormous potential of corilagin for control of PAD in humans.

Highlights

Due to an increase in the average age of the world population, peripheral artery disease (PAD) is the third-leading cause of atherosclerotic cardiovascular morbidity
We measured expression of the molecules involved in the toll-like receptor 4 (TLR4) signaling way [TLR4, toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP), myeloid differentiation factor (MyD)88, tumor necrosis factor receptorassociated factor (TRAF)6, nuclear factor-kappa B essential modulator (NEMO), mitogen-activated protein kinase p38 (p38), and interferon regulatory factor 5 (IRF5)] to discover the targets of their anti-atherosclerosis effects in vitro and in vivo
We found that TAK-242 could not effectively reduce the mRNA or protein expression of TLR4 and MyD88 compared to ox-LDL group

Summary

Introduction

Due to an increase in the average age of the world population, peripheral artery disease (PAD) is the third-leading cause of atherosclerotic cardiovascular morbidity. As one of the most common types of PAD, arteriosclerosis obliterans is characterized by pathologic changes of atherosclerosis in peripheral arteries with a series of ischemic symptoms [3]. The cells involved in the innate immune response (especially mononuclear macrophages) promote atherogenesis and regulate the stability of plaques in pivotal ways, such as participating in foam-cell formation, mediating the release and effects of cytokines, as well as interacting with endothelial cells and smooth muscle cells [5, 6]. Toll-like receptors (TLRs) are vital components of the innate immune system known for their ability to induce the inflammatory response at the outset [7]. A more important fact is that TLRs are considered to be associated with atherosclerosis through management of expression of some major molecules [8]

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