Tanyu Tongzhi Formula Delays Atherosclerotic Plaque Progression by Promoting Alternative Macrophage Activation via PPARγ and AKT/ERK Signal Pathway in ApoE Knock-Out Mice.

Lan Ma,Wei Mao,Mingshuang Li,Hongzhuan Sheng,Chenxia Wu,Xiaoce Dai

doi:10.3389/fphar.2021.734589

Abstract

We previously demonstrated that the Tanyu Tongzhi Formula (TTF) significantly alleviated the clinical symptoms of patients with coronary heart disease and lowered serum lipid and inflammatory factor levels in patients with coronary heart disease and atherosclerosis model rats. However, the mechanism underlying TTF remains unknown. In this study, we examined the effect of TTF on atherosclerotic plaques in ApoE-/- mice and underlying mechanisms involved in macrophage polarization. Sixty male ApoE-/- mice were randomly divided into four groups. Mice in the control group were fed a regular diet, whereas experimental mice were fed a high-fat diet and received either saline (HFD group) or TTF at concentrations of 0.60 (TTF-L group) or 2.25 g/ml (TTF-H group) by daily oral gavage for 16 weeks. In the TTF-L and TTF-H groups, the levels of serum cholesterol, triglyceride, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α were decreased, lipid content was significantly decreased, and percentage area of collagen/lipid increased in atherosclerotic plaque compared to in the HFD group. Moreover, we found TTF promoted the expression of alternative macrophage markers (Fizz1, Arg1, and Mrc) and suppressed the expression of M1 macrophage markers (TNF-α, IL-1β, and IL-6) by regulating peroxisome proliferator-activated receptor γ (PPARγ) expression and AKT/extracellular signal-regulated kinase (ERK) activation. We further investigated whether alternative macrophage was reduced when PPARγ was inhibited or the AKT/ERK signaling pathway was activated. TTF delayed atherosclerotic plaque progression by promoting alternative macrophage activation through increasing PPARγ expression and inhibiting AKT/ERK phosphorylation, providing a theoretical basis for its clinical application.

Highlights

The disability and fatality rate of cardiovascular diseases, such as coronary heart disease (CHD) and stroke rank first among non-communicable diseases, leading to large medical and economic burdens on society and individuals
The body weight of mice in the Tanyu Tongzhi Formula (TTF)-H group was decreased compared with the control group and high-fat diet (HFD) group from the 8th week of modeling (Figure 2B)
The four groups showed no significant difference in low-density lipoprotein-cholesterol (LDL-C) and high-density lipoproteincholesterol (HDL-C) levels

Summary

Introduction

The disability and fatality rate of cardiovascular diseases, such as coronary heart disease (CHD) and stroke rank first among non-communicable diseases, leading to large medical and economic burdens on society and individuals. Atherosclerosis (AS), the critical pathological basis of these diseases, is a chronic inflammatory disease characterized by narrowing of the blood vessels. The occurrence and development of AS are characterized by accumulation of various immune cells, release of different inflammatory factors, and formation of lipid and necrotic cores. Continued cell influx and proliferation lead to the more advanced lesions (Ross, 1993). Stimulation of different inflammatory factors in the microenvironment of the lesion induces macrophage polarization. When the number of inflammatory M1 macrophages increases and antiinflammatory alternative macrophages decrease, the lesion progresses. Macrophage polarization and inflammation, lipid metabolism, cell proliferation, and differentiation-related signaling pathways have been widely examined in the context of AS (Murray, 2017; Lin et al, 2018)

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