Abstract

Interferon regulatory factor 2 binding protein 2 (IRF2BP2) suppresses the innate inflammatory response of macrophages. A 9-nucleotide deletion (rs3045215) in the 3′ untranslated region (3′-UTR) of human IRF2BP2 mRNA confers risk of coronary artery disease (CAD) in the Ottawa Heart Genomics Study (OHGS). Here, we sought to identify regulatory mechanisms that may contribute to this risk. We tested how lipopolysaccharides (LPS) affects IRF2BP2 expression in human THP-1 macrophages and primary aortic smooth muscle cells (HAoSMC) genotyped for the deletion allele. Both cell types are implicated in coronary atherosclerosis. We also examined how the deletion affects interaction with RNA binding proteins (RBPs) to regulate IRF2BP2 expression. LPS altered allele-specific binding of RBPs in RNA gel shift assays with the THP-1 macrophage protein extracts. The RBP ELAVL1 suppressed the expression of a luciferase reporter carrying the 3′UTR of IRF2BP2 with the deletion allele. Other RBPs AUF1 or KHSRP did not confer such allele specific regulation. Since it is co-inherited with a risk variant for osteoporosis, a condition tied to arterial calcification, we examined the association of the deletion allele with coronary artery calcification in individuals who had undergone computed tomography angiography in the OHGS. In 323 individuals with a minimal burden of atherosclerosis (<30% coronary stenosis) and 138 CAD cases (>50% stenosis), Mendelian randomization revealed that the rs3045215 deletion allele significantly increased coronary artery calcification in men with minimal coronary stenosis. Thus, not only does the rs3045215 deletion allele predict atherosclerosis, but it also predisposes to early-onset calcification in men.

Highlights

  • Inflammatory macrophages play a central role in atherosclerosis [1] and are emerging as an important component of osteoporosis [2]

  • human aortic smooth muscle cells (HAoSMC) from HET donors showed a delayed reduction in Interferon regulatory factor 2 binding protein 2 (IRF2BP2) expression with LPS treatment (Figure 1D)

  • We examined the effect of the rs3045215 deletion allele in the 3’UTR of IRF2BP2 on the modulation of IRF2BP2 protein expression by LPS in HAoSMC

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Summary

Introduction

Inflammatory macrophages play a central role in atherosclerosis [1] and are emerging as an important component of osteoporosis [2]. Atherosclerosis and osteoporosis are two conditions that predispose to coronary artery calcification [3, 4]. Induction of interferon regulatory factor 1 (IRF1) plays a key role in the activation of the inflammatory response to LPS [7] by binding to cis-regulatory DNA sequences of interferon-responsive genes. Under basal conditions, these interferon-responsive genes are suppressed by competitive binding of the related factor IRF2 that is constitutively expressed [8]. IRF2 owes its repressor function to its interaction with IRF2 binding protein 2 (IRF2BP2) [9] that recruits the corepressors NCOR1 [10] and VGLL4 [11]

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