Regulatory Factor X1 Downregulation Contributes to Monocyte Chemoattractant Protein-1 Overexpression in CD14+ Monocytes via Epigenetic Mechanisms in Coronary Heart Disease.

Shuang Yang,Pei Du,Sujie Jia,Ming Zhao,Keqin Gao,Yu Cao,Baige Yao,Ren Guo

doi:10.3389/fgene.2019.01098

Abstract

Monocyte chemoattractant protein 1 (MCP1) affects the chemotaxis of monocytes and is a key chemokine closely related to the development of atherosclerosis (AS). Compared with healthy controls, coronary heart disease (CAD) patients show significantly upregulated plasma concentrations and mRNA expression of MCP1 in CD14+ monocytes. However, the specific regulatory mechanism of MCP1 overexpression in AS is still unclear. Our previous research indicated that there was no significant difference in the H3K4 and H3K27 tri-methylation of the MCP1 promoter in CD14+ monocytes from CAD versus non-CAD patients, but the H3 and H4 acetylation of the MCP1 promoter was increased in CD14+ monocytes from CAD patients. We further found that the H3K9 tri-methylation of the MCP1 promoter in CD14+ monocytes from CAD patients was decreased, but the DNA methylation levels did not differ markedly from those in non-CAD patients. Our previous work showed that the level of regulatory factor X1 (RFX1) was markedly reduced in CD14+ monocytes from CAD patients and played an important role in the progression of AS by regulating epigenetic modification. In this study, we investigated whether RFX1 and epigenetic modifications mediated by RFX1 contribute to the overexpression of MCP1 in activated monocytes in CAD patients. We found that the enrichment of RFX1, histone deacetylase 1 (HDAC1), and suppressor of variegation 3–9 homolog 1 (SUV39H1) in the MCP1 gene promoter region were decreased in CD14+ monocytes from CAD patients and in healthy CD14+ monocytes treated with low-density lipoprotein (LDL). Chromatin immunoprecipitation (ChIP) assays identified MCP1 as a target gene of RFX1. Overexpression of RFX1 increased the recruitments of HDAC1 and SUV39H1 and inhibited the expression of MCP1 in CD14+ monocytes. In contrast, knockdown of RFX1 in CD14+ monocytes reduced the recruitments of HDAC1 and SUV39H1 in the MCP1 promoter region, thereby facilitating H3 and H4 acetylation and H3K9 tri-methylation in this region. In conclusion, our results indicated that RFX1 expression deficiency in CD14+ monocytes from CAD patients contributed to MCP1 overexpression via a deficiency of recruitments of HDAC1 and SUV39H1 in the MCP1 promoter, which highlighted the vital role of RFX1 in the pathogenesis of CAD.

Highlights

Coronary heart disease (CAD) is the predominant cause of mortality worldwide (Chistiakov et al, 2016)
Our previous study showed that the levels of H3 and H4 acetylation in the promoter region of the Monocyte chemoattractant protein-1 (MCP1) gene in CD14+ monocytes was significantly higher in patients with CAD than in nonCAD patients (Xiao et al, 2018)
Research on human carotid endarterectomy showed that the MCP1 mRNA level detected by in situ hybridization was higher in organizing thrombi and in macrophage-rich areas than in normal arteries, which suggested an effect of MCP1 on mediating monocyte infiltration into artery wall (Nelken et al, 1991)

Summary

Introduction

Coronary heart disease (CAD) is the predominant cause of mortality worldwide (Chistiakov et al, 2016). Numerous studies have demonstrated that increased expression of MCP1 is closely related to the development of AS both in vivo and in vitro. Inhibition of MCP1 reduces monocyte adhesion and decreases lesion size both in vitro and in mice that overexpress human apolipoprotein B (Gosling et al, 1999). Monocytes may be involved in the amplification of their own recruitment to inflammatory lesions by inducing MCP1 (Cushing and Fogelman, 1992). A previous study showed a significant increase in MCP1 expression in CAD patients and LDL-treated monocytes (Du et al, 2019). The specific regulatory mechanisms of MCP1 overexpression in CD14+ monocytes are not fully understood

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Conclusion