OKL38 is an oxidative stress response gene stimulated by oxidized phospholipids.
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.
Li
Rongsong
R
Department of Pathology and Medicine, University of California, Los Angeles, CA 90095, USA. rli@mednet.ucla.edu
Chen
Wendy
W
Yanes
Rolando
R
Lee
Sangderk
S
Berliner
Judith A
JA
D000098:Acetophenones / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010713:Phosphatidylcholines / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism
D000098:Acetophenones; D051017:Apoptosis Regulatory Proteins; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; C432368:OSGIN1 protein, human; D010713:Phosphatidylcholines; D010743:Phospholipids; D011506:Proteins; D034741:RNA, Small Interfering; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D013481:Superoxides; C056165:acetovanillone; C018855:2-tert-butylhydroquinone; D019255:NADPH Oxidases