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 b (Ab) stimulates platelet aggregation, we studied whether L5 and Ab function synergistically to induce prothrombotic pathways leading to stroke. Levels of plasma L5, serum Ab, 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 phosphatebuffered saline treatment. Deficiency or neutralizing of LOX-1 reduced infarct volume up to threefoldafter focal cerebral ischemiainmice, illustrating the importanceofLOX-1in stroke injury. In human platelets, L5 but not L1 (the least electronegative LDL subfraction) induced Ab release via IkBkinase 2 (IKK2). Furthermore, L51Ab synergistically induced glycoprotein IIb/IIIa receptor activation; phosphorylation of IKK2, IkBa, p65, and c-Jun N-Terminal kinase 1; and platelet aggregation. These effectswere blockedby inhibiting IKK2,LOX-1,ornuclear factor'kB(NF-kB). InjectingL51Abshortenedtail-bleeding timeby50%(n512;P<.05vsL1-injected mice), which was prevented by the IKK2 inhibitor. Our findings suggest that, through LOX-1, atherogenic L5 potentiates Abmediated platelet activation, platelet aggregation, and hemostasis via IKK2/NF-kB signaling. L5 elevationmay be a risk factor for cerebral atherothrombosis, anddownregulating LOX-1 and inhibiting IKK2maybe novel antithrombotic strategies. (Blood.