Lipoxin A4 and its analog attenuate high fat diet-induced atherosclerosis via Keap1/Nrf2 pathway

Fen Xu; Jiamin Zhang; Xiaoyan Zhou; Hua Hao

doi:10.1016/j.yexcr.2022.113025

Lipoxin A₄ and its analog attenuate high fat diet-induced atherosclerosis via Keap1/Nrf2 pathway

Exp Cell Res. 2022 Mar 1;412(1):113025. doi: 10.1016/j.yexcr.2022.113025. Epub 2022 Jan 10.

Authors

Fen Xu¹, Jiamin Zhang², Xiaoyan Zhou³, Hua Hao⁴

Affiliations

¹ Department of General Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, PR China; Medical Examination Center, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, PR China.
² Department of Pathophysiology, Medical College of Nanchang University, Nanchang, Jiangxi, 330006, PR China.
³ Department of Pathophysiology, Medical College of Nanchang University, Nanchang, Jiangxi, 330006, PR China. Electronic address: zhouxiaoyan@ncu.edu.cn.
⁴ Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, PR China. Electronic address: haohua410@126.com.

PMID: 35026282
DOI: 10.1016/j.yexcr.2022.113025

Abstract

Excessive oxidative stress and decreased antioxidant capacity of macrophages are initial factors which cause macrophages to transform to foam cells, which represents a key event in the progression of atherosclerosis (AS). BML-111, the analog of lipoxin A₄ (LXA₄) strongly attenuated high fat (HF) diet-induced atherosclerosis by activating NF-E2 related factor 2 (Nrf2). However, the effect was not through a specific LXA₄ receptor (formyl peptide receptor 2, FPR2). BML-111 also strongly inhibited HF diet-induced promotion of MDA level, increased HDL level and decreased IL-1, MCP-1, IL-6, VCAM, ICAM and TNF-α level in aorta. In the in vitro experiments, LXA₄ inhibited THP-1 cells to transform to foam cells via Nrf2 pathway. Our findings demonstrated that LXA₄ and its analog prevented AS induced by HF diet in SD rats, under which the possible mechanism is through Keap1/Nrf2 pathway.

Keywords: Atherosclerosis; Inflammation; Lipoxin; Nrf2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atherosclerosis / etiology
Atherosclerosis / metabolism*
Atherosclerosis / prevention & control*
Diet, High-Fat / adverse effects
Disease Models, Animal
Foam Cells / drug effects
Foam Cells / metabolism
Foam Cells / pathology
Heptanoic Acids / pharmacology*
Humans
Kelch-Like ECH-Associated Protein 1 / metabolism*
Lipoxins / pharmacology*
Male
NF-E2-Related Factor 2 / metabolism*
Oxidative Stress / drug effects
Rats
Rats, Sprague-Dawley
Receptors, Lipoxin / metabolism
Signal Transduction / drug effects
THP-1 Cells

Substances

5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester
Heptanoic Acids
KEAP1 protein, rat
Kelch-Like ECH-Associated Protein 1
Lipoxins
NF-E2-Related Factor 2
Nfe2l2 protein, rat
Receptors, Lipoxin
lipoxin A(4) receptor, rat
lipoxin A4