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

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.

• Authors: Ming-Yi Shen, Fang-Yu Chen, Jing-Fang Hsu, Ru-Huei Fu, Chia-Ming Chang, Chiz-Tzung Chang, Chung-Hsiang Liu, Jia-Rong Wu, An-Sheng Lee, Hua-Chen Chan, Joen-Rong Sheu, Shinn-Zong Lin, Woei-Cherng Shyu, Tatsuya Sawamura, Kuan-Cheng Chang, Chung Y Hsu, Chu-Huang Chen
• Journal: Blood (Blood) Vol. 127 Issue 10 Pg. 1336-45 (Mar 10 2016) ISSN: 1528-0020 [Electronic] United States
• PMID: 26679863 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society of Hematology.

Chemical References

• 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

Topics

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