Catalpol Inhibits Macrophage Polarization and Prevents Postmenopausal Atherosclerosis Through Regulating Estrogen Receptor Alpha.

Yuhan Zhang,Qi Chen,Huimin Bian,Yunhui Bi,Yu Li,Weiwei Zhang,Xu Qi,Qinghai Meng

doi:10.3389/fphar.2021.655081

Abstract

Lacking estrogen increases the risk of atherosclerosis (AS) in postmenopausal women. Inflammation plays a vital role in the pathological process of AS, and macrophages are closely related to inflammation. Catalpol is an iridoid glucoside extracted from the fresh roots of the traditional Chinese herb Rehmanniae radix preparata. In this study, we aimed to evaluate the effects of catalpol on macrophage polarization and postmenopausal AS. In addition, we investigated whether the mechanism of catalpol was dependent on regulating the expression of estrogen receptors (ERs). In vitro, lipopolysaccharides (LPS) and interferon-γ (IFN-γ) were applied to induce M1 macrophage polarization. In vivo, the ApoE−/− mice were fed with a high-fat diet to induce AS, and ovariectomy was operated to mimic the estrogen cessation. We demonstrated catalpol inhibited M1 macrophage polarization induced by LPS and INF-γ, and eliminated lipid accumulation in postmenopausal AS mice. Catalpol not only suppressed the inflammatory response but also reduced the level of oxidative stress. Then, ERs (ERα and ERβ) inhibitors and ERα siRNA were also applied in confirming that the protective effect of catalpol was mediated by ERα, rather than ERβ. In conclusion, catalpol significantly inhibited macrophage polarization and prevented postmenopausal AS by increasing ERα expression.

Highlights

Atherosclerosis (AS) is closely related to inflammation and the disorder of lipid metabolism (Feng et al, 2020; van Leent et al, 2021)
The pro-inflammatory cytokine IL-6 secreted by J774A-1 increased significantly after the treatment with LPS&INF-γ, and the level of IL-6 was effectively attenuated by E2 and catalpol (Figure 1C)
They can degrade the extracellular matrix by secreting several matrix metalloproteinases (MMPs), which cause instability and rupture in plaques

Summary

Introduction

Atherosclerosis (AS) is closely related to inflammation and the disorder of lipid metabolism (Feng et al, 2020; van Leent et al, 2021). Inflammation promotes the change of endothelial cell function Wang et al (2013), which results in the release of pro-inflammatory factors, as well as the monocyte chemokines. The increase of pro-inflammatory factors in the vessel leads leukocytes to infiltrate into the arteries. Stimulated by chemokines, the monocytes in peripheral blood migrate to the endothelium and differentiate into macrophages (Vieceli Dalla Sega et al, 2019). The activation of macrophages is relevant to the expression of inflammatory cytokines and the release of reactive oxygen species (ROS). With the decline of migration ability, the activated macrophages phagocytose modified lipoproteins and damaged cells (Orekhov et al, 2020). Macrophages contain more cholesterol and differentiate into foam cells, which persist in plaques and promote the progress of AS (Cybulsky et al, 2016)

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