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

Blood. 2016 Mar 10;127(10):1336-45. doi: 10.1182/blood-2015-05-646117. Epub 2015 Dec 17.

Abstract

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 IκB kinase 2 (IKK2). Furthermore, L5+Aβ synergistically induced glycoprotein IIb/IIIa receptor activation; phosphorylation of IKK2, IκBα, p65, and c-Jun N-terminal kinase 1; and platelet aggregation. These effects were blocked by inhibiting IKK2, LOX-1, or nuclear factor-κB (NF-κB). 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-κB signaling. L5 elevation may be a risk factor for cerebral atherothrombosis, and downregulating LOX-1 and inhibiting IKK2 may be novel antithrombotic strategies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / blood
  • Animals
  • Brain Ischemia / blood*
  • Brain Ischemia / pathology
  • Disease Models, Animal
  • Female
  • Humans
  • I-kappa B Kinase / metabolism
  • Intracranial Arteriosclerosis / blood
  • Intracranial Arteriosclerosis / pathology
  • Intracranial Thrombosis / blood
  • Intracranial Thrombosis / pathology
  • Lipoproteins, LDL / blood*
  • Male
  • Mice
  • Mice, Knockout
  • Platelet Aggregation*
  • Scavenger Receptors, Class E / metabolism
  • Signal Transduction
  • Stroke / blood*
  • Stroke / pathology

Substances

  • Amyloid beta-Peptides
  • Lipoproteins, LDL
  • OLR1 protein, human
  • Olr1 protein, mouse
  • Scavenger Receptors, Class E
  • low-density lipoprotein L5, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • Ikbkb protein, mouse