OKL38 is an oxidative stress response gene stimulated by oxidized phospholipids

Rongsong Li,Wendy Chen,Rolando Yanes,Sangderk Lee,Judith A Berliner

doi:10.1194/jlr.m600501-jlr200

Abstract

Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) is present in oxidative modified LDL and accumulates in lesions of many chronic inflammatory diseases, such as atherosclerosis. In a microarray study, OxPAPC has been demonstrated to modulate the expression of >700 genes in human aortic endothelial cells. We found that the levels of mRNA for OKL38 [also named Bone marrow Derived Growth Factor (BDGI)], a tumor growth inhibitor, were strongly increased by OxPAPC. Here, we report that OKL38 is regulated by an oxidative signal induced by OxPAPC and its component lipid 1-palmitoyl-2-epoxyisoprostane E2-sn-glycero-3-phosphorylcholine. The stimulation of OKL38 by OxPAPC depends on superoxide production, because the NADPH oxidase (Nox) inhibitor apocynin and the superoxide scavenger N-acetyl cysteine block this stimulation. Oxidative stress by tert-butylhydroquinone treatment also induced the expression of OKL38. The stimulation of OKL38 expression by OxPAPC is mediated via transcription factor nuclear factor E2-related factor (Nrf2), a common factor involved in the regulation of oxidative stress-stimulated genes. Activation of Nrf2 induces the expression of OKL38, whereas small interfering RNA knockdown of Nrf2 blocks the stimulation of OKL38 by OxPAPC. Our results suggest that OKL38 is regulated via the Nox/Nrf2 pathway in response to oxidative stress stimuli.

Highlights

Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero3-phosphorylcholine (OxPAPC) is present in oxidative modified LDL and accumulates in lesions of many chronic inflammatory diseases, such as atherosclerosis
We report that OxPAPC stimulates the expression of OKL38 in endothelial cells, monocytes, and macrophages and that the stimulation of OKL38 expression requires the activation of NADPH oxidase (Nox) and nuclear factor E2-related factor (Nrf2)
To confirm the regulation of OKL38 by OxPAPC, human aortic endothelial cell (HAEC) were treated with OxPAPC and the expression of OKL38 was analyzed by real-time PCR (Fig. 1A)

Summary

Introduction

Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero3-phosphorylcholine (OxPAPC) is present in oxidative modified LDL and accumulates in lesions of many chronic inflammatory diseases, such as atherosclerosis. OxPAPC was demonstrated to regulate the expression of .700 genes in human aortic endothelial cells (HAECs) [8]. Nuclear factor E2-related factor (Nrf2) has been shown to be a major transcription factor that mediates ROS- and oxidative stress-induced gene expression [17]. We examine the regulation of OKL38 by OxPAPC and the role of oxidative signal and Nrf2.

Results

Conclusion