2-(2-Phenylethyl)Chromone-Enriched Extract of Chinese Agarwood (Aquilaria Sinensis) Inhibits Atherosclerosis Progression Through Endoplasmic Reticulum Stress-Mediated Cd36 Expression in Macrophages

Abstract

Background: Oxidized low-density lipoprotein (oxLDL) triggers scavenger receptor CD36 to induce foam cell formation from macrophages play a pivotal role in atherosclerosis (AS) progression. However, the action of endoplasmic reticulum stress (ER stress) on oxLDL-regulated CD36 expression is still unclear.

Purpose: The goal of this study is to elucidate whether endoplasmic reticulum (ER) stress participate the CD36-modulated foam cell formation. The anti-atherosclerotic efficacy of 2-(2-phenylethyl)chromone-enriched extract of Chinese agarwood (CPE) was elucidated simultaneously by ER tress-mediated CD36 pathway.

Methods: The inhibition of CPE on the scope of cellular lipids loading was assessed after differentiated THP-1 macrophages were exposed to oxLDL firstly. Then the function of CPE on the expression patterns of scavenger receptors and ER stress were then characterized. The atherosclerotic mouse model was emerged with ApoE−/− mice by using the high-fat diet regimen to examine the efficacy of CPE.Results: CPE inhibited oxLDL uptake and foam cells formation of macrophages by decreasing scavenger receptor CD36 in oxLDL-induced THP-1 macrophages. Moreover, We confirmed that the overexpression of CD36 triggered by oxLDL was regulated by activation of JNK1/2/3 and ER stress. To clarify the efficacy of CPE in vivo, atherosclerotic ApoE−/− mice was established by using the high-fat diet regimen. The results show that CPE suppressed aortic plaque of ApoE−/− mice and the upregulated ER stress and CD36 in plaque.

Conclusion: In summary, ER stress/P-JNK/PPARγ/CD36 signaling pathway play an important role on oxLDL induced overexpression of scavenger receptor CD36 in vitro and in vivo. CPE inhibited the foam cell formation through alleviating ER stress meditated CD36 expression, providing a potential therapeutic medicine for AS.

Note:
Funding declaration: This work was supported by the National Natural Science Foundation of China (Grant No. 82074050), and the Beijing Natural Science Foundation (7232296).

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: All the experiments were approved by the medical animal experiment ethics committee of the Beijing University of Chinese Medicine (Approval Number: BUCM-4-2015080501-3001).

Keywords: Chinese agarwood, 2-(2-Phenylethyl) Chromone, ER stress, CD36