Alteration of lysophosphatidylcholine content in low density lipoprotein after oxidative modification: relationship to endothelium dependent relaxation

Liu, S.-Y.; Lü, Xiaoli; Choy, Steve; Dembinski, Thomas C.; Hatch, Grant M.; Mymin, David; Shen, X.; Ángel, A.; Choy, Patrick C.; Man, Ryk

doi:10.1093/cvr/28.10.1476

Cited by 69 publications

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“…The OxLDL with higher LPC content showed a greater impairment in endothelium-dependent relaxation of aortic rings than did LDL with lower LPC content. 19 How does LPC activate PYK2 after a Western diet? LPC directly binds to G-protein-coupled receptors, which consist of G2A, with higher affinity, and GPR4, with lower affinity.…”

Section: Discussionmentioning

confidence: 99%

Early Inflammatory Reactions in Atherosclerosis Are Induced by Proline-Rich Tyrosine Kinase/Reactive Oxygen Species–Mediated Release of Tumor Necrosis Factor-α and Subsequent Activation of the p21 ^Cip1 /Ets-1/p300 System

Katsume

Okigaki

Matsui

et al. 2011

ATVB

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Objective-Reactive oxygen species (ROS) are involved in the initial process of atherosclerosis, whereas it remains to be determined how atherogenic stimulus causes ROS-mediated proinflammatory reactions. Here, we focused on proline-rich tyrosine kinase (PYK2)-mediated ROS generation and examined how atherogenic stimulus causes early proinflammatory reactions. Methods and Results-PYK2-deficient (knockout [KO]) (PYK2-KO) mice were crossbred with apolipoprotein E (ApoE)-deficient (PYK2-KO/ApoE-KO) mice. PYK2-KO/ApoE-KO mice and endothelial cells (EC) were used for the study. Aortic atherogenic lesions in PYK2-KO/ApoE-KO mice were markedly decreased (55% versus ApoE-KO) after 8 weeks of a Western diet. Aortic PYK2 was activated as early as 7 days after the Western diet, when inflammatory cellswere not yet activated. Addition of the proatherogenic oxidized phospholipid lysophosphatidylcholine caused activation of endothelial PYK2. Lysophosphatidylcholine-activated PYK2 induced NADPH oxidase-mediated ROS generation and ROS-mediated synthesis of tumor necrosis factor-␣ (TNF␣), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1), and p21 Cip1 /Ets-1. Neutralizing anti-TNF␣ antibody or knockdown of p21 Cip1 /Ets-1 system blocked the induction of VCAM-1 and MCP-1. PYK2 deficiency abolished these ROS-mediated proinflammatory reactions. Further analysis revealed that PYK2/ROS-mediated p21Cip1 /Ets-1 activation upregulated the transcription of the MCP-1 gene in collaboration with p300 transcription coactivator. Conclusion-PYK2 is a key tyrosine kinase activated by high cholesterol exposure, which causes ROS-mediated TNF␣ release and induces TNF␣-dependent expression of proinflammatory molecules via the p21 Cip1 /Ets-1/p300 transcription system. (Arterioscler Thromb Vasc Biol. 2011;31:1084-1092.)

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Section: Discussionmentioning

confidence: 99%

Early Inflammatory Reactions in Atherosclerosis Are Induced by Proline-Rich Tyrosine Kinase/Reactive Oxygen Species–Mediated Release of Tumor Necrosis Factor-α and Subsequent Activation of the p21 ^Cip1 /Ets-1/p300 System

Katsume

Okigaki

Matsui

et al. 2011

ATVB

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“…Lp-PLA2 uses OxPLs, which are incidentally transported by Lp(a), as substrate and produces lysophosphatidylcholine (LPC). 9 Also, through nonenzymatic pathways, the oxidation of LDLs generates LPC, 10,11 a highly reactive metabolite with proosteogenic properties and present in mineralized aortic valves. 8,12 Autotaxin (ATX), encoded by the ENPP2 gene, is a lysophospholipase D enzyme that is transported in the blood plasma and secreted by different cell populations.…”

Section: August 25 2015mentioning

confidence: 99%

Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve

et al. 2015

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The main process that triggers pathological mineralization of the aortic valve remains elusive. 3 Recently, 3 successive studies with a Mendelian randomization design have reported a significant association between the LPA gene variant (rs10455872), which genetically determines the lipoprotein(a) [Lp(a)] plasma level, and CAVD. [4][5][6] These studies thus suggested a causal relationship between Lp(a) and CAVD risk. Lp(a) is a low-density lipoprotein (LDL)-like particle in which an apolipoprotein(a) is linked by a disulfide bridge to apolipoprotein B. Lp(a) is a major carrier of oxidized phospholipids (OxPLs) and has been associated Background-Mendelian randomization studies have highlighted that lipoprotein(a) [Lp(a)] was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids with a high content in lysophosphatidylcholine. Autotaxin (ATX) transforms lysophosphatidylcholine into lysophosphatidic acid. We hypothesized that ATXlysophosphatidic acid could promote inflammation/mineralization of the aortic valve. Methods and Results-We have documented the expression of ATX in control and mineralized aortic valves. By using different approaches, we have also investigated the role of ATX-lysophosphatidic acid in the mineralization of isolated valve interstitial cells and in a mouse model of CAVD. Enzyme-specific ATX activity was elevated by 60% in mineralized aortic valves in comparison with control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which colocalized with oxidized phospholipids and apolipoprotein(a). We detected a high level of ATX activity in the Lp(a) fraction in circulation. Interaction between ATX and Lp(a) was confirmed by in situ proximity ligation assay. Moreover, we documented that valve interstitial cells also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promotes the mineralization of the aortic valve through a nuclear factor κB/interleukin 6/bone morphogenetic protein pathway. In LDLR -/-/ApoB 100/100 /IGFII mice, ATX is overexpressed and lysophosphatidic acid promotes a strong deposition of hydroxyapatite of calcium in aortic valve leaflets and accelerates the development of CAVD. Conclusions-ATX

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“…Thus, expression of Lp-PLA 2 in activated macrophages will probably lead to the release in atherosclerotic lesions of lyso-PC and free oxidatively modified fatty acids in potentially large quantities. Several biological activities have been assigned to increased lyso-PC content, such as chemoattractant activity for human monocytes, 5 endothelial dysfunction, 18,44 induction of the expression of endothelial leukocyte adhesion molecules, 7 and increased expression of plateletderived growth factor and heparin-binding epidermal growth factor-like proteins. 17 Thus, although preventing the proposed biological activities of PAF-like substances, Lp-PLA 2 could augment the atherosclerotic process by releasing into the microenvironment increased concentrations of lyso-PC and oxidatively modified free fatty acids from oxidized LDL.…”

Section: Human and Rabbit Atherosclerotic Samples Used For In Situ Hymentioning

confidence: 99%

Lipoprotein-Associated Phospholipase A ₂ , Platelet-Activating Factor Acetylhydrolase, Is Expressed by Macrophages in Human and Rabbit Atherosclerotic Lesions

Häkkinen

Luoma²,

Hiltunen³

et al. 1999

ATVB

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Abstract-We studied the expression of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), an enzyme capable of hydrolyzing platelet-activating factor (PAF), PAF-like phospholipids, and polar-modified phosphatidylcholines, in human and rabbit atherosclerotic lesions. Oxidative modification of low-density lipoprotein, which plays an important role in atherogenesis, generates biologically active PAF-like modified phospholipid derivatives with polar fatty acid chains. PAF is known to have a potent proinflammatory activity and is inactivated by its hydrolysis. On the other hand, lysophosphatidylcholine and oxidized fatty acids released from oxidized low-density lipoprotein as a result of Lp-PLA 2 activity are thought to be involved in the progression of atherosclerosis. Using combined in situ hybridization and immunocytochemistry, we detected Lp-PLA 2 mRNA and protein in macrophages in both human and rabbit atherosclerotic lesions. Reverse transcriptase-polymerase chain reaction analysis indicated an increased expression of Lp-PLA 2 mRNA in human atherosclerotic lesions. In addition, Ϸ6-fold higher Lp-PLA 2 activity was detected in atherosclerotic aortas of Watanabe heritable hyperlipidemic rabbits compared with normal aortas from control rabbits. It is concluded that (1) macrophages in both human and rabbit atherosclerotic lesions express Lp-PLA 2 , which could cleave any oxidatively modified phosphatidylcholine present in the lesion area, and (2) modulation of Lp-PLA 2 activity could lead to antiatherogenic effects in the vessel wall.

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Alteration of lysophosphatidylcholine content in low density lipoprotein after oxidative modification: relationship to endothelium dependent relaxation

Cited by 69 publications

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Early Inflammatory Reactions in Atherosclerosis Are Induced by Proline-Rich Tyrosine Kinase/Reactive Oxygen Species–Mediated Release of Tumor Necrosis Factor-α and Subsequent Activation of the p21 ^Cip1 /Ets-1/p300 System

Early Inflammatory Reactions in Atherosclerosis Are Induced by Proline-Rich Tyrosine Kinase/Reactive Oxygen Species–Mediated Release of Tumor Necrosis Factor-α and Subsequent Activation of the p21 ^Cip1 /Ets-1/p300 System

Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve

Lipoprotein-Associated Phospholipase A ₂ , Platelet-Activating Factor Acetylhydrolase, Is Expressed by Macrophages in Human and Rabbit Atherosclerotic Lesions

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Alteration of lysophosphatidylcholine content in low density lipoprotein after oxidative modification: relationship to endothelium dependent relaxation

Cited by 69 publications

References 0 publications

Early Inflammatory Reactions in Atherosclerosis Are Induced by Proline-Rich Tyrosine Kinase/Reactive Oxygen Species–Mediated Release of Tumor Necrosis Factor-α and Subsequent Activation of the p21 Cip1 /Ets-1/p300 System

Early Inflammatory Reactions in Atherosclerosis Are Induced by Proline-Rich Tyrosine Kinase/Reactive Oxygen Species–Mediated Release of Tumor Necrosis Factor-α and Subsequent Activation of the p21 Cip1 /Ets-1/p300 System

Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve

Lipoprotein-Associated Phospholipase A 2 , Platelet-Activating Factor Acetylhydrolase, Is Expressed by Macrophages in Human and Rabbit Atherosclerotic Lesions

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Early Inflammatory Reactions in Atherosclerosis Are Induced by Proline-Rich Tyrosine Kinase/Reactive Oxygen Species–Mediated Release of Tumor Necrosis Factor-α and Subsequent Activation of the p21 ^Cip1 /Ets-1/p300 System

Early Inflammatory Reactions in Atherosclerosis Are Induced by Proline-Rich Tyrosine Kinase/Reactive Oxygen Species–Mediated Release of Tumor Necrosis Factor-α and Subsequent Activation of the p21 ^Cip1 /Ets-1/p300 System

Lipoprotein-Associated Phospholipase A ₂ , Platelet-Activating Factor Acetylhydrolase, Is Expressed by Macrophages in Human and Rabbit Atherosclerotic Lesions