| First Author | Shen MY | Year | 2016 |
| Journal | Blood | Volume | 127 |
| Issue | 10 | Pages | 1336-45 |
| PubMed ID | 26679863 | Mgi Jnum | J:232591 |
| Mgi Id | MGI:5779604 | Doi | 10.1182/blood-2015-05-646117 |
| Citation | Shen MY, et al. (2016) Plasma L5 levels are elevated in ischemic stroke patients and enhance platelet aggregation. Blood 127(10):1336-45 |
| abstractText | 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 (Abeta) stimulates platelet aggregation, we studied whether L5 and Abeta function synergistically to induce prothrombotic pathways leading to stroke. Levels of plasma L5, serum Abeta, 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 Abeta release via IkappaB kinase 2 (IKK2). Furthermore, L5+Abeta synergistically induced glycoprotein IIb/IIIa receptor activation; phosphorylation of IKK2, IkappaBalpha, p65, and c-Jun N-terminal kinase 1; and platelet aggregation. These effects were blocked by inhibiting IKK2, LOX-1, or nuclear factor-kappaB (NF-kappaB). Injecting L5+Abeta 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 Abeta-mediated platelet activation, platelet aggregation, and hemostasis via IKK2/NF-kappaB signaling. L5 elevation may be a risk factor for cerebral atherothrombosis, and downregulating LOX-1 and inhibiting IKK2 may be novel antithrombotic strategies. |
