Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation

Abstract

Key Points• Highly electronegative LDL (L5), which is elevated in patients with STEMI, induces platelet activation and aggregation through LOX-1.• L5 may have a role in promoting thrombogenesis that leads to STEMI.Platelet activation and aggregation underlie acute thrombosis that leads to ST-elevation myocardial infarction (STEMI). L5-highly electronegative low-density lipoprotein (LDL)-is significantly elevated in patients with STEMI. Thus, we examined the role of L5 in thrombogenesis. Plasma LDL from patients with STEMI (n 5 30) was chromatographically resolved into 5 subfractions (L1-L5) with increasing electronegativity. In vitro, L5 enhanced adenosine diphosphate-stimulated platelet aggregation twofold more than did L1 and induced platelet-endothelial cell (EC) adhesion. L5 also increased P-selectin expression and glycoprotein (GP)IIb/IIIa activation and decreased cyclic adenosine monophosphate levels (n 5 6, P < .01) in platelets. In vivo, injection of L5 (5 mg/kg) into C57BL/6 mice twice weekly for 6 weeks shortened tail bleeding time by 43% (n 5 3; P < .01 vs L1-injected mice) and increased P-selectin expression and GPIIb/IIIa activation in platelets. Pharmacologic blockade experiments revealed that L5 signals through plateletactivating factor receptor and lectin-like oxidized LDL receptor-1 to attenuate Akt activation and trigger granule release and GPIIb/IIIa activation via protein kinase C-a. L5 but not L1 induced tissue factor and P-selectin expression in human aortic ECs (P < .01), thereby triggering platelet activation and aggregation with activated ECs. These findings indicate that elevated plasma levels of L5 may promote thrombosis that leads to STEMI. (Blood. 2013;122(22):3632-3641)

Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo

“…Therefore, these findings imply that cellular senescence may mediate endothelial dysfunction and atherogenesis after chronic exposure to a sublethal level of L5. In other studies, we have shown that the concentration of L5 is less than 10 μg/ml in healthy individuals and is 100 μg/ml in patients with acute myocardial infarction (Chan et al., 2013), 20 μg/ml in patients with chronic kidney disease (Chang et al., 2013, 2016), and 100 μg/ml in patients with hypercholesterolemia (Chen et al., 2003). These estimations indicate that the concentration of L5 chosen for our in vitro experiments is the same order of magnitude as the concentration detected in humans, suggesting that our findings may be clinically relevant.…”

“…These estimations indicate that the concentration of L5 chosen for our in vitro experiments is the same order of magnitude as the concentration detected in humans, suggesting that our findings may be clinically relevant. In addition, we previously found that the percentage of L5 in total LDL from patients with myocardial infarction was around 15% (Chan et al., 2013), which is equivalent to an L5 plasma level of approximately 15 mg/dl. If the effects of redistribution and plasma protein binding are omitted, the dosage of L5 used to inject the mice (2 mg kg −1  day −1 ) would presumably reach a plasma concentration of 15 mg/dl.…”

“…In addition, serum levels of L5 were found to be significantly increased in patients with ST‐elevation myocardial infarction or stroke (Chan et al., 2013; Chang et al., 2013; Shen et al., 2015). In this study, we have further examined the biologic effects of L5 and have explored the possible involvement of L5 in premature vascular endothelial senescence.…”

Interplay between CRP, Atherogenic LDL, and LOX-1 and Its Potential Role in the Pathogenesis of Atherosclerosis

“…This highly electronegative LDL has been called L5 because it is the fifth, most electronegative subfraction of LDL isolated by using anion-exchange chromatography (23 ). Plasma concentrations of L5 have been shown to be significantly increased in patients with cardiovascular risks, including smokers and patients with diabetes mellitus and hypercholesterolemia (23)(24)(25), and L5 concentrations are increased to an even greater extent in the plasma of patients with ST-elevation myocardial infarction (26 ).…”

Chemical composition of circulating native and desialylated low density lipoprotein: what is the difference?

“…[ [21][22][23][24] On the other hand, recent studies showed that LDL(-) had an ability to induce anti-inflammatory cytokines [e.g. interleukin-10 (IL-10)] and counteract inflammatory effects promoted by lipopolysaccharides.…”