TY - JOUR
T1 - Identification of a novel series of anti-inflammatory and anti-oxidative phospholipid oxidation products containing the cyclopentenone moiety in vitro and in vivo
T2 - Implication in atherosclerosis
AU - Lu, Jianhong
AU - Guo, Shuyuan
AU - Xue, Xinli
AU - Chen, Qun
AU - Ge, Jing
AU - Zhuo, Yujuan
AU - Zhong, Huiqin
AU - Chen, Buxing
AU - Zhao, Mingming
AU - Han, Wei
AU - Suzuki, Takashi
AU - Zhu, Mingjiang
AU - Xia, Lin
AU - Schneider, Claus
AU - Blackwell, Timothy S.
AU - Porter, Ned A.
AU - Zheng, Lemin
AU - Tsimikas, Sotirios
AU - Yin, Huiyong
N1 - Funding Information:
This work was supported by grants from the National Natural Science Foundation of China (31470831, 91439103, 91539127, 21402221, 31170809, and 31671231), Ministry of Science and Technology of China (2016YFC0903403, 2016YFD0400205, and 2012CB524905), and Hundred Talents Program from the Chinese Academy of Sciences (2012OHTP07). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All of the sequence reads of this study were deposited in the Sequence Reads Archive at the NCBI database under accession number GSE85931.1 Received financial support from National Institutes of Heath Grant GM 076592.
PY - 2017/3/31
Y1 - 2017/3/31
N2 - 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-isoprostanesphosphocholine, from 1-palmitoyl-2-arachidonoyl-sn-glycero- 3-phosphocholine in vivo using 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.
AB - 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-isoprostanesphosphocholine, from 1-palmitoyl-2-arachidonoyl-sn-glycero- 3-phosphocholine in vivo using 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.
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U2 - 10.1074/jbc.M116.751909
DO - 10.1074/jbc.M116.751909
M3 - Article
C2 - 28202546
AN - SCOPUS:85016571366
SN - 0021-9258
VL - 292
SP - 5378
EP - 5391
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 13
ER -