title: Identification of a novel series of anti-inflammatory and anti-oxidative phospholipid oxidation products containing the cyclopentenone moietyin vitroandin vivo: Implication in atherosclerosis.
abstract: Oxidative stress and inflammation are two major contributing factors to atherosclerosis, a leading cause of cardiovascular disease. Oxidation of phospholipids on the surface of low density lipoprotein (LDL) particles generated under oxidative stress has been associated with the progression of atherosclerosis, but the underlying molecular mechanisms remain poorly defined. We identified a novel series of oxidation products containing the cyclopentenone moiety, termed deoxy-A2/J2-isoprostanes-phosphocholine, from 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholinein vivousing mass spectrometry and by comparison to a chemically synthesized standard. Transcriptomic analysis (RNA-seq) demonstrated that these compounds affected >200 genes in bone marrow-derived macrophages, and genes associated with inflammatory and anti-oxidative responses are among the top 5 differentially expressed. To further investigate the biological relevance of these novel oxidized phospholipids in atherosclerosis, we chemically synthesized a representative compound 1-palmitoyl-2-15-deoxy-δ-12,14-prostaglandin J2-sn-glycero-3-phosphocholine (15d-PGJ2-PC) and found that it induced anti-inflammatory and anti-oxidant responses in macrophages through modulation of NF-κB, peroxisome proliferator-activated receptor γ (PPARγ), and Nrf2 pathways; this compound also showed potent anti-inflammatory properties in a mice model of LPS-induced systematic inflammatory response syndrome. Additionally, 15d-PGJ2-PC inhibited macrophage foam cell formation, suggesting a beneficial role against atherosclerosis. These properties were consistent with decreased levels of these compounds in the plasma of patients with coronary heart disease compared with control subjects. Our findings uncovered a novel molecular mechanism for the negative regulation of inflammation and positive enhancement of anti-oxidative responses in macrophages by these oxidized phospholipids in LDL in the context of atherosclerosis.
authors.affiliation: From the Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100000, China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Lu
authors.affiliation: From the Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100000, China.|School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Guo
authors.affiliation: From the Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100000, China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Xue
authors.affiliation: From the Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100000, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ge
authors.affiliation: From the Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100000, China.|School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Zhuo
authors.affiliation: From the Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100000, China.
authors.forename: Huiqin
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Buxing
authors.initials: B
authors.lastname: Chen
authors.affiliation: Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Medicine.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology.
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: From the Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100000, China.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Zhu
authors.affiliation: From the Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100000, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xia
authors.affiliation: Division of Clinical Pharmacology, Department of Pharmacology.
authors.forename: Claus
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Department of Medicine.|Department of Cancer Biology, and.|Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.|Department of Veterans Affairs, Nashville, Tennessee 37232.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, and.
authors.forename: Ned A
authors.initials: NA
authors.lastname: Porter
authors.affiliation: Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Lemin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, California 92093.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.affiliation: From the Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, hyyin@sibs.ac.cn.|University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100049, China.|Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100000, China.|School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Yin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism*; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D003517:Cyclopentanes / Q000378:metabolism; D005487:Foam Cells; D006801:Humans; D007249:Inflammation; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D010743:Phospholipids / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D003517:Cyclopentanes; D008077:Lipoproteins, LDL; D010743:Phospholipids; C013905:cyclopentenone
keywords: atherosclerosis; free radicals; inflammation; isoprostane; lipid peroxidation