Plasma L5 levels are elevated in ischemic stroke patients and enhance platelet activation and aggregation

L5, the most electronegative, atherogenic subfraction of low-density lipoprotein (LDL), induces platelet activation. We hypothesized that plasma L5 levels are increased in acute ischemic stroke patients, and we 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 beta (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<0.01). In mice, L5 treatment resulted in larger infarction volumes but only in those with LOX-1. Deficiency or neutralizing of LOX-1 reduced infarct volume up to 3-fold after focal cerebral ischemic 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 GPIIb/IIIa receptor activation; phosphorylation of IKK2, IκBα, p65, and c-Jun N-terminal kinase 1 (JNK1); and platelet aggregation— effects blocked by inhibiting IKK2, LOX-1, or nuclear factor kappa B (NF-κB). Injecting L5+Aβ shortened tail-bleeding time by 50% (n=12; P<0.05 vs. L1-injected mice), which was prevented by IKK2 inhibitor. Our findings suggest that atherogenic L5, through LOX-1, 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 down-regulating LOX-1 or inhibiting IKK2 may be novel anti-thrombotic strategies. For personal use only. on September 14, 2017. by guest www.bloodjournal.org From