title: Plasma L5 levels are elevated in ischemic stroke patients and enhance platelet aggregation.
abstract: L5, the most electronegative and atherogenic subfraction of low-density lipoprotein (LDL), induces platelet activation. We hypothesized that plasma L5 levels are increased in acute ischemic stroke patients and examined whether lectin-like oxidized LDL receptor-1 (LOX-1), the receptor for L5 on endothelial cells and platelets, plays a critical role in stroke. Because amyloid β (Aβ) stimulates platelet aggregation, we studied whether L5 and Aβ function synergistically to induce prothrombotic pathways leading to stroke. Levels of plasma L5, serum Aβ, and platelet LOX-1 expression were significantly higher in acute ischemic stroke patients than in controls without metabolic syndrome (P < .01). In mice subjected to focal cerebral ischemia, L5 treatment resulted in larger infarction volumes than did phosphate-buffered saline treatment. Deficiency or neutralizing of LOX-1 reduced infarct volume up to threefold after focal cerebral ischemia in mice, illustrating the importance of LOX-1 in stroke injury. In human platelets, L5 but not L1 (the least electronegative LDL subfraction) induced Aβ release via IκB kinase 2 (IKK2). Furthermore, L5+Aβ synergistically induced glycoprotein IIb/IIIa receptor activation; phosphorylation of IKK2, IκBα, p65, and c-Jun N-terminal kinase 1; and platelet aggregation. These effects were blocked by inhibiting IKK2, LOX-1, or nuclear factor-κB (NF-κB). Injecting L5+Aβ shortened tail-bleeding time by 50% (n = 12; P < .05 vs L1-injected mice), which was prevented by the IKK2 inhibitor. Our findings suggest that, through LOX-1, atherogenic L5 potentiates Aβ-mediated platelet activation, platelet aggregation, and hemostasis via IKK2/NF-κB signaling. L5 elevation may be a risk factor for cerebral atherothrombosis, and downregulating LOX-1 and inhibiting IKK2 may be novel antithrombotic strategies.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Medicine Research, China Medical University Hospital, Taichung, Taiwan; Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Shen
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Medicine Research, China Medical University Hospital, Taichung, Taiwan; Division of Cardiology, China Medical University Hospital, Taichung, Taiwan;
authors.forename: Fang-Yu
authors.initials: FY
authors.lastname: Chen
authors.affiliation: Department of Public Health, China Medical University, Taichung, Taiwan; Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan;
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Immunology, China Medical University, Taichung, Taiwan;
authors.forename: Ru-Huei
authors.initials: RH
authors.lastname: Fu
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Medicine Research, China Medical University Hospital, Taichung, Taiwan;
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan;
authors.forename: Chiz-Tzung
authors.initials: CT
authors.lastname: Chang
authors.affiliation: Department of Neurology, and China Medical University Hospital, Taichung, Taiwan;
authors.forename: Chung-Hsiang
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan;
authors.forename: Jia-Rong
authors.initials: JR
authors.lastname: Wu
authors.affiliation: Division of Cardiology, China Medical University Hospital, Taichung, Taiwan; Department of Medicine, Mackay Medical College, New Taipei, Taiwan;
authors.forename: An-Sheng
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan;
authors.forename: Hua-Chen
authors.initials: HC
authors.lastname: Chan
authors.affiliation: Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
authors.affiliation: Graduate Institute of Immunology, China Medical University, Taichung, Taiwan; Department of Neurology, and China Medical University Hospital, Taichung, Taiwan;
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
authors.affiliation: Graduate Institute of Immunology, China Medical University, Taichung, Taiwan; Department of Neurology, and China Medical University Hospital, Taichung, Taiwan;
authors.forename: Woei-Cherng
authors.initials: WC
authors.lastname: Shyu
authors.affiliation: Department of Physiology, Shinshu University School of Medicine, Asahi, Matsumoto, Japan;
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawamura
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Division of Cardiology, China Medical University Hospital, Taichung, Taiwan;
authors.forename: Kuan-Cheng
authors.initials: KC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Department of Neurology, and China Medical University Hospital, Taichung, Taiwan;
authors.forename: Chung Y
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; Center for Lipid Biosciences, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Vascularand Medicinal Research, Texas Heart Institute, Houston, TX; New York Heart Research Foundation, Mineola, NY; Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; and Lipid and Glycoimmune Research Center, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Chu-Huang
authors.initials: CH
authors.lastname: Chen
mesh_terms: D016229:Amyloid beta-Peptides / Q000097:blood; D000818:Animals; D002545:Brain Ischemia / Q000097:blood* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D002537:Intracranial Arteriosclerosis / Q000097:blood / Q000473:pathology; D020767:Intracranial Thrombosis / Q000097:blood / Q000473:pathology; D008077:Lipoproteins, LDL / Q000097:blood*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010974:Platelet Aggregation; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D015398:Signal Transduction; D020521:Stroke / Q000097:blood* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; C495138:Olr1 protein, mouse; D051127:Scavenger Receptors, Class E; C574964:low-density lipoprotein L5, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496562:Ikbkb protein, mouse