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Novel phosphatidylethanolamine derivatives accumulate in circulation in hyperlipidemic ApoE-/- mice and activate platelets via TLR2
被引:38
作者:

Biswas, Sudipta
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Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA

Xin, Liang
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h-index: 0
机构:
Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA

Panigrahi, Soumya
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Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA

Zimman, Alejandro
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机构:
Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA

Wang, Hua
论文数: 0 引用数: 0
h-index: 0
机构:
Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA

Yakubenko, Valentin P.
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Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA

Byzova, Tatiana V.
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Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA

Salomon, Robert G.
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机构:
Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA

Podrez, Eugene A.
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h-index: 0
机构:
Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA
机构:
[1] Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA
来源:
基金:
美国国家卫生研究院;
关键词:
TOLL-LIKE RECEPTORS;
LUNG MICROVASCULAR ENDOTHELIA;
FAMILY KINASE ACTIVATION;
LOW-DENSITY-LIPOPROTEIN;
OXIDIZED PHOSPHOLIPIDS;
INNATE IMMUNITY;
STRUCTURAL IDENTIFICATION;
TYROSINE PHOSPHORYLATION;
PARACELLULAR PATHWAY;
ENDOGENOUS LIGANDS;
D O I:
10.1182/blood-2015-08-664300
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
A prothrombotic state and increased platelet reactivity are common in dyslipidemia and oxidative stress. Lipid peroxidation, a major consequence of oxidative stress, generates highly reactive products, including hydroxy-omega-oxoalkenoic acids that modify autologous proteins generating biologically active derivatives. Phosphatidylethanolamine, the second most abundant eukaryotic phospholipid, can also be modified by hydroxy-omega-oxoalkenoic acids. However, the conditions leading to accumulation of such derivatives in circulation and their biological activities remain poorly understood. We now show that carboxyalkylpyrrole-phosphatidylethanolamine derivatives (CAP-PEs) are present in the plasma of hyperlipidemic ApoE(-/-) mice. CAP-PEs directly bind to TLR2 and induces platelet integrin alpha(IIb)beta(3) activation and P-selectin expression in a Toll-like receptor 2 (TLR2)-dependent manner. Platelet activation by CAP-PEs includes assembly of TLR2/TLR1 receptor complex, induction of downstream signaling via MyD88/TIRAP, phosphorylation of IRAK4, and subsequent activation of tumor necrosis factor receptor-associated factor 6. This in turn activates the Src family kinases, spleen tyrosine kinase and PLC gamma 2, and platelet integrins. Murine intravital thrombosis studies demonstrated that CAP-PEs accelerate thrombosis in TLR2-dependent manner and that TLR2 contributes to accelerate thrombosis in mice in the settings of hyperlipidemia. Our study identified the novel end-products of lipid peroxidation, accumulating in circulation in hyperlipidemia and inducing platelet activation by promoting cross-talk between innate immunity and integrin activation signaling pathways.
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页码:2618 / 2629
页数:12
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Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA

Bannerman, Douglas D.
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USDA, Bovine Funct Genom Lab, Beltsville, MD 20705 USA Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA

Vogel, Stefanie N.
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Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA

Goldblum, Simeon E.
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Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA
Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA
Univ Maryland, Dept Med, Baltimore, MD 21201 USA Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA
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Bioactive aldehyde-modified phosphatidylethanolamines
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Guo, Lilu
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Davies, Sean S.
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BIOCHIMIE,
2013, 95 (01)
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Guo, Lilu
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Vanderbilt Univ, Dept Pharmacol, Div Clin Pharmacol, Nashville, TN 37232 USA Vanderbilt Univ, Dept Pharmacol, Div Clin Pharmacol, Nashville, TN 37232 USA

Davies, Sean S.
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Vanderbilt Univ, Dept Pharmacol, Div Clin Pharmacol, Nashville, TN 37232 USA Vanderbilt Univ, Dept Pharmacol, Div Clin Pharmacol, Nashville, TN 37232 USA