Original ArticleCYP2J2 Overexpression Increases EETs and Protects Against HFD-Induced Atherosclerosis in ApoE−/− MiceLiu, Wanjun PhD; Wang, Tao PhD; He, Xingwei MD; Liu, Xintian PhD; Wang, Bei PhD; Liu, Yujian MD; Li, Zhuxi MS; Tan, Rong MS; Ding, Chen MD; Wang, Hongjie MD, PhD; Zeng, Hesong MD, PhDAuthor Information The Institute of Hypertension and Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, China. Reprints: Hesong Zeng, MD, PhD, Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Avenue, Wuhan 430030, China (e-mail: email@example.com). Supported by the National Nature Science Foundation of China (No. 81170259) and Key Project of Health Ministration. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org). W. Liu and T. Wang contributed equally to this work. Received September 17, 2015 Accepted January 15, 2016 Journal of Cardiovascular Pharmacology: June 2016 - Volume 67 - Issue 6 - p 491-502 doi: 10.1097/FJC.0000000000000371 Buy SDC Metrics Abstract Aims: The aim of the present study was to investigate how cytochrome P450 (CYP)2J2–derived epoxyeicosatrienoic acids (EETs) regulate the AKT1 and FOXO1 and BIM pathway and protect against endothelial apoptosis in the development and progression of atherosclerosis. Methods and Results: Recombinant adeno-associated virus (rAAV)-mediated CYP2J2 overexpression increased EET levels and prevented high-fat diet–induced atherosclerosis in ApoE−/− mice, which was associated with reduced vascular apoptosis. We also observed that CYP2J2 overexpression suppressed the weight gain induced by a high-fat diet. In vitro CYP2J2 overexpression increased EET levels, subsequently preventing tumor necrosis factor-α–induced apoptosis in human umbilical vein endothelial cells (HUVECs), which contributed to the pathogenesis of atherosclerosis. We observed that AKT1 suppressed BIM expression and apoptosis by inhibiting the function of FOXO1 in cultured HUVECs. Furthermore, we found that CYP2J2 overexpression and its metabolic products, EETs, suppressed tumor necrosis factor-α–induced apoptosis through AKT1 and FOXO1 and BIM dependent signaling in HUVECs. Conclusions: In summary, we identified a novel molecular mechanism for CYP2J2-derived EETs to protect against atherosclerosis. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.