The Anti-inflammatory Effect of Soluble Epoxide Hydrolase Inhibitor and 14, 15-EET in Kawasaki Disease Through PPARγ/STAT1 Signaling Pathway.

Na Dai,Xiaoyue Liu,Minmin Wang,Cuifen Zhao,Qing Fan,Chunyan Yang,Haizhao Zhao

doi:10.3389/fped.2020.00451

Abstract

Soluble epoxide hydrolase (sEH) is responsible for rapid degradation of 14, 15-EET, which is one of the isomers of EETs and plays an important role in cardiovascular diseases. In this study, we investigated the mechanism by which sEH inhibitor AUDA played an anti-inflammatory effect in HCAECs. Our results indicated that AUDA treatment promoted PPARγ expression, while knockdown of PPARγ blocked the cell growth and STAT1 expression inhibition induced by 100 μmol/L AUDA in HCAECs. AUDA also inhibited the overexpression of TNF-α, IL-1 β, and MMP-9 induced by KD sera in HCAECs. Moreover, 30 blood samples from children with Kawasaki disease (KD) were collected with 30 healthy children as the control group. QPCR and ELISA assays were used to detect the level of 14, 15-EET, TNF-α, IL-1β, and MMP-9. We found that the level of 14, 15-EET was higher in peripheral blood of children with KD compared with healthy controls (P < 0.05). In comparison to KD children with non-coronary artery lesion (nCAL), the level of 14, 15-EET was higher in peripheral blood of KD children with coronary artery lesion (CAL) (P < 0.05). Compared with healthy control group, the expression levels of TNF-α, IL-1β, and MMP-9 in patients with KD were significantly up-regulated. Compared with nCAL KD children, the expression levels of TNF-α, IL-1β, and MMP-9 in CAL children were abnormally high (P < 0.05). Our study indicated that AUDA played an anti-inflammatory effect in HCAECs through PPARγ/STAT1 signaling pathway, and 14, 15-EET is up-regulated in children with KD, suggesting that 14, 15-EET involved in the progression of KD.

Highlights

Studies have shown that arachidonic acid (ARA) is converted to endogenous lipid EETs by P450 arachidonic acid cyclooxygenase (ARA cyclooxygenase), while EETs are converted to inactive DHET by Soluble epoxide hydrolase (sEH) in vivo [1, 2]
To investigate the mechanism by which AUDA played an antiinflammatory effect, we detected the mRNA level of PPARγ in Human Coronary Arterial Endothelial Cells (HCAECs) using Quantitative Real-Time PCR (qPCR)
The results show that the overexpression of PPARγ did not affect the effect of AUDA compared with the AUDA group (P < 0.05, Figure 1)

Summary

Introduction

Studies have shown that arachidonic acid (ARA) is converted to endogenous lipid EETs by P450 arachidonic acid cyclooxygenase (ARA cyclooxygenase), while EETs are converted to inactive DHET by sEH in vivo [1, 2]. 14, 15-EET plays an important role in cardiovascular diseases [4, 5]. A number of studies have shown that 14, 15-EET promotes PDGF-induced proliferation of porcine aortic smooth muscle cells by inhibiting. We found that AUDA, a sEH inhibitor, could inhibit the expression of MMP-9, IL-1β, and TNF-α in vitro and in vivo, protecting and repairing myocardial injury [7]. We explored the specific mechanism of AUDA in the process of myocardial protection. This study provides evidence for the clinical treatment of KD targeted by EETs

Methods

Results

Conclusion