Impact Factor 3.831

Frontiers journals are at the top of citation and impact metrics

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01105

Paeonol Attenuated Inflammatory Response of Endothelial Cells via Stimulating Monocytes-derived Exosomal MicroRNA-223

 Yarong Liu1, 2,  Chao Li1,  Hongfei Wu1, 2, Xianmei Xie1, Ying Sun1 and  Min Dai1, 2*
  • 1Anhui University of Chinese Medicine, China
  • 2Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, China

Introduction: Paeonol, an active compound isolated from the radix of Cortex Moutan, has been shown to have anti-atherosclerosis effects by regulating blood cells’ function and protecting vascular cells injury. Besides, emerging evidences has proven that exosomes might play a pivotal role in intercellular communication by transmiting proteins and microRNAs from cell to cell. However, the relationship between monocytes-derived exosomal microRNA-223 and vascular inflammation injury along with paeonol’ effects are still not clear.
Objective: Our study aimed to explain whether paeonol’s protective effect on inflammatory response is related to the regulation of exosomal microRNA-223 in the VECs.
Methods: ApoE-/- mice were fed with high fat diet to replicate the AS model. HE staining and immunohistochemistry was used to detect inflammatory response of aorta. The expression of IL-1β and IL-6 were detected by ELISA. Western blot was used to detect the expression of STAT3, pSTAT3, ICAM-1 and VCAM-1. qRT-PCR was used to detect miR-223 expression. Exosomes were extracted from THP-1 cells by differential centrifugation and observed by transmission electron microscope. Observation of exosomes uptake into HUVECs was realized by laser microscopy. MiR-223 target gene was detected by double luciferase gene report test.
Results: In vivo experiments confirmed that paeonol restricted atherosclerosis development and increased miR-223 expression, inhibited STAT3 pathway in ApoE-/- mice. In vitro, miR-223 showed robust presence in THP-1 cells and undetectable in HUVECs. And we had observed that miR-223 could be internalized from THP-1 cells into HUVECs taking exosomes as a carrier. Paeonol obviously increased miR-223 expression in co-cultured HUVECs and exosomes in concentration dependent manner, compared to LPS group. In addition, paeonol relieved inflammatory secretion, adhesion and STAT3 expression in HUVECs, which could be inverted after miR-223 inhibitor transfection into THP-1 cells.
Conclusion: Paeonol could increase the expression of miR-223 in THP-1 derived exosomes and in HUVECs after uptake of exosomes, whereas decrease the expression of STAT3, p-STAT3 in HUVECs. Ultimately paeonol decreased the expression of IL-1β, IL-6, ICAM-1, VCAM-1 in HUVECs and alleviated adhesion of THP-1 cells to HUVECs.

Keywords: paeonol, Atherosclerosis, lipopolysaccharide, Exosomes, MicroRNA-223, stat3, Monocytes, Endothelial Cells

Received: 29 Jun 2018; Accepted: 10 Sep 2018.

Edited by:

Li-Long Pan, Fudan University, China

Reviewed by:

Wei Wei, Anhui Medical University, China
Houkai Li, Shanghai University of Traditional Chinese Medicine, China
Min Hong, Nanjing University of Chinese Medicine, China  

Copyright: © 2018 Liu, Li, Wu, Xie, Sun and Dai. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Min Dai, Anhui University of Chinese Medicine, Hefei, China, daiminliao@163.com