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

被引:38
作者
Biswas, Sudipta [1 ]
Xin, Liang [2 ]
Panigrahi, Soumya [1 ]
Zimman, Alejandro [1 ]
Wang, Hua [2 ]
Yakubenko, Valentin P. [1 ]
Byzova, Tatiana V. [1 ]
Salomon, Robert G. [2 ]
Podrez, Eugene A. [1 ]
机构
[1] Cleveland Clin, Dept Mol Cardiol, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA
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.
引用
收藏
页码:2618 / 2629
页数:12
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