Changzhou No. 2 People's Hospital, Diabetes Institute, 29 Xinglong Lane, Changzhou City, Jiangsu Prov. 213003, China.
Department of Medicine, University of California, Los Angeles, 650 Charles Young Dr., Los Angeles, CA 90095, USA.
Biochem Biophys Res Commun. 2014 Jan 31;444(1):69-74. doi: 10.1016/j.bbrc.2014.01.016. Epub 2014 Jan 14.
Atherosclerosis is the main underlying cause of major cardiovascular diseases such as stroke and heart attack. Oxidized phospholipids such as oxidized 1-palmitoyl-2-arachidonoyl-sn-Glycero-3-phosphorylcholine (OxPAPC) accumulate in lesions of and promote atherosclerosis. OxPAPC activates endothelial cells, a critical early event of atherogenesis. Epoxyisoprostane E2 (EI) is an oxidized fatty acid contained at the sn-2 position of 1-palmitoyl-2-epoxyisoprostane E2-sn-glycero-3-phosphorylcholine (PEIPC), the most active component of OxPAPC in regulating inflammation. OxPAPC and its components including PEIPC activate endothelial cells to express an array of genes in different categories including oxidative stress response genes such as tumor suppressor gene OKL38 and Heme oxygenase-1 (HO-1). EI can be released by lipase from PEIPC. In this study, we examined the ability of EI to stimulate oxidative stress response in endothelial cells. EI released from OxPAPC and synthetic EI stimulated the expression of oxidative stress response gene OKL38 and antioxidant gene HO-1. Treatment of endothelial cells with EI increased the production of superoxide. NADPH oxidase inhibitor Apocynin and superoxide scavenger N-acetyl-cysteine (NAC) significantly attenuated EI-stimulated expression of OKL38 and HO-1. We further demonstrated that EI activated oxidative stress-sensitive transcription factor Nrf2. Silencing of Nrf2 with siRNA significantly reduced EI stimulated expression of OKL38 and HO-1. Thus, we demonstrated that EI induced oxidative stress in endothelial cells leading to increased expression of oxidative stress response gene OKL38 and HO-1 via Nrf2 signaling pathway relevant to atherosclerosis.
动脉粥样硬化是中风和心脏病等主要心血管疾病的主要潜在原因。氧化磷脂，如氧化 1-棕榈酰-2-花生四烯酰-sn-甘油-3-磷酸胆碱（OxPAPC），在病变部位积累并促进动脉粥样硬化。OxPAPC 激活内皮细胞，这是动脉粥样硬化发生的关键早期事件。环氧异前列腺素 E2（EI）是 1-棕榈酰-2-环氧异前列腺素 E2-sn-甘油-3-磷酸胆碱（PEIPC）中 sn-2 位置的氧化脂肪酸，PEIPC 是调节炎症的 OxPAPC 中最活跃的成分。OxPAPC 及其成分，包括 PEIPC，激活内皮细胞表达一系列不同类别的基因，包括肿瘤抑制基因 OKL38 和血红素加氧酶-1（HO-1）等氧化应激反应基因。EI 可以通过脂肪酶从 PEIPC 中释放出来。在这项研究中，我们研究了 EI 刺激内皮细胞氧化应激反应的能力。OxPAPC 和合成 EI 释放的 EI 刺激氧化应激反应基因 OKL38 和抗氧化基因 HO-1 的表达。EI 处理内皮细胞增加了超氧化物的产生。NADPH 氧化酶抑制剂 Apocynin 和超氧化物清除剂 N-乙酰半胱氨酸（NAC）显著减弱了 EI 刺激的 OKL38 和 HO-1 的表达。我们进一步证明 EI 激活了氧化应激敏感转录因子 Nrf2。用 siRNA 沉默 Nrf2 显著降低了 EI 刺激的 OKL38 和 HO-1 的表达。因此，我们证明 EI 诱导内皮细胞氧化应激，导致氧化应激反应基因 OKL38 和 HO-1 的表达增加，这与动脉粥样硬化相关的 Nrf2 信号通路有关。
