Activation-Dependent Surface Expression of LOX-1 in Human Platelets

Chen, Mingyi; Kakutani, Makoto; Naruko, Takahiko; Ueda, Makiko; Narumiya, Shuh; Masaki, Τοmoh; Sawamura, Tatsuya

doi:10.1006/bbrc.2001.4516

Cited by 152 publications

(103 citation statements)

References 33 publications

(47 reference statements)

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“…More recent studies have indicated that LOX-1 is expressed in other cells types, including macrophages (2), vascular smooth-muscle cells (3), and platelets (4). Its expression is not constitutive, but rather, markedly induced by proinflammatory, oxidative, and mechanical stimuli (5,6), which leads to the activation of endothelial cells, transformation of smooth-muscle cells, and accumulation of lipids in macrophages, resulting in cellular injury and the development of atherosclerosis.…”

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confidence: 99%

The hydrophobic tunnel present in LOX-1 is essential for oxidized LDL recognition and binding

Francone

Royer

et al. 2009

Journal of Lipid Research

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Lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1) is a type-II transmembrane protein that belongs to the C-type lectin family of molecules. LOX-1 acts as a cell surface endocytosis receptor and mediates the recognition and internalization of ox-LDL by vascular endothelial cells. Internalization of ox-LDL by LOX-1 results in a number of pro-atherogenic cellular responses implicated in the development and progression of atherosclerosis. In an effort to elucidate the functional domains responsible for the binding of ox-LDL to the receptor, a series of site-directed mutants were designed using computer modeling and X-ray crystallography to study the functional role of the hydrophobic tunnel present in the LOX-1 receptor. The isoleucine residue (I 149 ) sitting at the gate of the channel was replaced by phenylalanine, tyrosine, or glutamic acid to occlude the channel opening and restrict the docking of ligands to test its functional role in the binding of ox-LDL. The synthesis, intracellular processing, and cellular distribution of all mutants were identical to those of wild type, whereas there was a marked decrease in the ability of the mutants to bind ox-LDL. These studies suggest that the central hydrophobic tunnel that extends through the entire LOX-1 molecule is a key functional domain of the receptor and is critical for the recognition of modified LDL. Lectin-like oxidized LDL receptor-1 (LOX-1) is a member of the class E scavenger receptor family, a structurally diverse group of cell surface receptors of the innate immune system that recognize and internalize oxidized LDL (ox-LDL) in endothelial cells of large arteries (1). More recent studies have indicated that LOX-1 is expressed in other cells types, including macrophages (2), vascular smooth-muscle cells (3), and platelets (4). Its expression is not constitutive, but rather, markedly induced by proinflammatory, oxidative, and mechanical stimuli (5, 6), which leads to the activation of endothelial cells, transformation of smooth-muscle cells, and accumulation of lipids in macrophages, resulting in cellular injury and the development of atherosclerosis. Studies in animal models have provided further evidence in support of a role for LOX-1 in atherosclerosis. Overexpression of LOX-1 in mice leads to the formation of atheroma-like lesion areas (7). Conversely, its deletion sustains endothelial function and confers protection in the development of atherosclerosis in association with decreased inflammatory and pro-oxidant markers (8). Finally, human genetic studies strengthen the role of this receptor in cardiovascular disease (9-11).LOX-1 is a disulfide-linked homodimeric type II transmembrane protein with a short 34-residue cytoplasmic tail, a single transmembrane domain, and an extracellular region consisting of an 80-residue domain predicted to be a coil followed by a 130-residue C-terminal C-type lectinlike domain (CTLD) responsible for ox-LDL recognition (12)(13)(14). Homodimers are formed via an interchain disulfide bond between Cys 140 residu...

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confidence: 99%

The hydrophobic tunnel present in LOX-1 is essential for oxidized LDL recognition and binding

Francone

Royer

et al. 2009

Journal of Lipid Research

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“…6 Immunohistochemical staining for LOX-1 has been identified in thrombus associated with atherosclerotic plaque obtained from a patient with unstable angina. 6 Based upon these findings, LOX-1 is considered to be involved in platelet activation and thrombus formation after plaque erosion or rupture that results in acute coronary syndrome (ACS). As far as I can ascertain, no reports have yet identified more LOX-1 in the coronary plaques of patients with than without ACS.…”

Section: Article P 1433mentioning

confidence: 99%

Paradigm Shift From Myocardium-Derived to Plaque-Derived Biomarkers for Very Early Diagnosis of Acute Myocardial Infarction

Imamura

2011

Circ J

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“…LOX-1 has been reported to be expressed in endothelial cells, monocyte/macrophages, platelets, and vascular smooth muscle cells (VSMCs) as well as in renal, pulmonary and neuronal tissues. LOX-1 expression can be induced by oxLDL, free radicals (reactive oxygen species), endothelin-1 (ET-1), angiotensin II, advanced glycation end-products (AGEs) and shear stress (10)(11)(12) Departments of 1 Neurology, atherosclerosis contribute to the induction of LOX-1 expression (13,14). ET-1 has been suggested to be involved in the pathogenesis of cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

Berberine combined with atorvastatin downregulates LOX-1 expression through the ET-1 receptor in monocyte/macrophages

Chi

et al. 2014

International Journal of Molecular Medicine

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Abstract. Studies have shown that the oxidative modification of low-density lipoprotein (oxLDL) plays a major role in atherogenesis. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mediated the transport of oxLDL into macrophages, which promoted foam cell formation. Targeting LOX-1 may therefore be a promising approach to inhibit atherosclerosis. In the present study, we aimed to investigate the effect of berberine combined with atorvastatin on LOX-1 and explore the underlying molecular mechanism involved. Expression of LOX-1 in monocyte-derived macrophages (MDMs) exposed to berberine (0, 0.1, 1, 10 and 100 nM) and atorvastatin (100 nM) were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis. Results showed that the expression of LOX-1 was decreased in a dose-dependent manner. Additionally, knockdown of the endothelin-1 (ET-1) receptor significantly blocked the inhibitory effect of berberine on LOX-1 expression. Body weight (BW), liver weight (LW) and kidney weight (KW) in the model rats were markedly increased at concentrations of berberine ≥1 µmol/kg, while heart weight (HW) and spleen weight (SW) remained constant among all groups. Berberine combined with atorvastatin also decreased serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C) levels in the rat model as well as inflammation and oxidative stress. Furthermore, plasma ET-1 levels and LOX-1 expression were decreased by berberine combined with atorvastatin treatment, and the inhibitory effect on LOX-1 was impeded by an ET-1 receptor antagonist. The results demonstrated that berberine combined with atorvastatin downregulates LOX-1 expression through ET-1 receptors in monocyte/macrophages in vitro and in vivo.

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Activation-Dependent Surface Expression of LOX-1 in Human Platelets

Cited by 152 publications

References 33 publications

The hydrophobic tunnel present in LOX-1 is essential for oxidized LDL recognition and binding

The hydrophobic tunnel present in LOX-1 is essential for oxidized LDL recognition and binding

Paradigm Shift From Myocardium-Derived to Plaque-Derived Biomarkers for Very Early Diagnosis of Acute Myocardial Infarction

Berberine combined with atorvastatin downregulates LOX-1 expression through the ET-1 receptor in monocyte/macrophages

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