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

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 beta (A beta) stimulates platelet aggregation, we studied whether L5 and A beta function synergistically to induce prothrombotic pathways leading to stroke. Levels of plasma L5, serum A beta, 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 A beta release via I kappa B kinase 2 (IKK2). Furthermore, L5+A beta synergistically induced glycoprotein IIb/IIIa receptor activation; phosphorylation of IKK2, I kappa B alpha, p65, and c-Jun N-terminal kinase 1; and platelet aggregation. These effectswere blocked by inhibiting IKK2, LOX-1, or nuclear factor-kappa B (NF-kappa B). Injecting L5+A beta 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 A beta-mediated platelet activation, platelet aggregation, and hemostasis via IKK2/NF-kappa B signaling. L5 elevation may be a risk factor for cerebral atherothrombosis, and downregulating LOX-1 and inhibiting IKK2 may be novel antithrombotic strategies.