OKL38 is an oxidative stress response gene stimulated by oxidized phospholipids

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 stressstimulated 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.-Li, R., W. Chen, R. Yanes, S. Lee, and J. A. Berliner. OKL38 is an oxidative stress response gene stimulated by oxidized phospholipids. J. Lipid Res. 2007. 48: 709-715.

Evidence for the importance of OxPAPC interaction with cysteines in regulating endothelial cell function

“…The similarity of structure in these two molecules suggested that they might have similar interactions with cell proteins. Previous studies have shown similar effects of 15dPGJ 2 to OxPAPC in several pathways ( 7,9,12,14,15,(22)(23)(24)(25)(26)(27). We now demonstrate that OxPNB and 15dPGJ 2 bind to the same cysteines in H-Ras (C181 and C184) and that 15dPGJ 2 can inhibit the binding of OxPNB to H-Ras.…”

Endothelial cell regulation by phospholipid oxidation products

“…A newly recognized anti-oxidant gene, OKL 38, is also induced by Ox-PAPC. Regulation of HO-1 transcription has been examined by two groups, who have identified two different pathways involved in this regulation: Kronke et al identified a MAP kinase/CREB pathway of activation in HUVEC 48 , while Li et al identified a pathway involving the activation of Nrf2 16 in HAEC. Induction of these antioxidant enzymes is likely to protect the cell from cell death, which is negligible in response to Ox-PAPC.…”

“…The array and cell biology studies have highlighted several transcription factors important in Ox-PAPC action, such as STAT3, SREBP, Nrf2, erg-1, NFAT and transcription factors of the UPR system. 15,16 In this review, we will address the roles of these transcription factors as well as other signaling molecules in Ox-PAPC signaling. Since Ox-PAPC contains a mixture of oxidized phospholipids, studies with the individual phospholipids have also been reported and will be discussed in this review.…”

Inflammation-Related Gene Expression by Lipid Oxidation Derived Products in the Progression of Atherosclerosis

“…In parallel with an increased production of ROS, oxPAPC may stimulate the transcription of oxidative stress response genes, such as OKL38, a key regulator of important inflammatory and anti-inflammatory molecules [201]. Expression of OKL38 has been observed to be mediated by Nrf2 [202].…”