title: Novel phosphatidylethanolamine derivatives accumulate in circulation in hyperlipidemic ApoE-/- mice and activate platelets via TLR2.
abstract: 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-ω-oxoalkenoic acids that modify autologous proteins generating biologically active derivatives. Phosphatidylethanolamine, the second most abundant eukaryotic phospholipid, can also be modified by hydroxy-ω-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 αIIbβ3 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 PLCγ2, 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.
authors.affiliation: Department of Molecular Cardiology, The Cleveland Clinic, Cleveland, OH; and.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, OH.
authors.forename: Liang
authors.initials: L
authors.lastname: Xin
authors.affiliation: Department of Molecular Cardiology, The Cleveland Clinic, Cleveland, OH; and.
authors.forename: Soumya
authors.initials: S
authors.lastname: Panigrahi
authors.affiliation: Department of Molecular Cardiology, The Cleveland Clinic, Cleveland, OH; and.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Zimman
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, OH.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular Cardiology, The Cleveland Clinic, Cleveland, OH; and.
authors.forename: Valentin P
authors.initials: VP
authors.lastname: Yakubenko
authors.affiliation: Department of Molecular Cardiology, The Cleveland Clinic, Cleveland, OH; and.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Byzova
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, OH.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Salomon
authors.affiliation: Department of Molecular Cardiology, The Cleveland Clinic, Cleveland, OH; and.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Podrez
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001792:Blood Platelets / Q000378:metabolism*; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D015539:Platelet Activation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010714:Phosphatidylethanolamines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; C493486:Tlr2 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; C483858:phosphatidylethanolamine; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse