Publication Date:
2016-03-11
Description:
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 IB kinase 2 (IKK2). Furthermore, L5+Aβ synergistically induced glycoprotein IIb/IIIa receptor activation; phosphorylation of IKK2, IBα, p65, and c-Jun N-terminal kinase 1; and platelet aggregation. These effects were blocked by inhibiting IKK2, LOX-1, or nuclear factor–B (NF-B). 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-B signaling. L5 elevation may be a risk factor for cerebral atherothrombosis, and downregulating LOX-1 and inhibiting IKK2 may be novel antithrombotic strategies.
Keywords:
Free Research Articles, Platelets and Thrombopoiesis, Thrombosis and Hemostasis
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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