Lectin-like oxidized-LDL receptor-1 (LOX-1) polymorphisms influence cardiovascular events rate during statin treatment

Puccetti, Luca; Pasqui, Anna Laura; Bruni, Fulvio; Pastorelli, Marcello; Ciani, F.; Palazzuoli, Alberto; Pontani, A; Ghezzi, A.; Auteri, Alberto

doi:10.1016/j.ijcard.2006.07.045

Cited by 18 publications

(13 citation statements)

References 36 publications

(51 reference statements)

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“…LOX-1 gene allelic variants (3 UTR/T) have been related to cardiovascular events and reduced antiplatelet activity induced by statins. A retrospective study performed in 751 white hypercholesterolemic subjects treated with increasing doses of atorvastatin revealed that LOX-1 polymorphisms influence cardiovascular events rate during statin treatment (Puccetti et al 2006).…”

Section: The Effects Of Antiatherosclerotic Drugsmentioning

confidence: 99%

Lectin‐like Oxidized Low‐density Lipoprotein Receptor‐1, a New Promising Target for the Therapy of Atherosclerosis?

Chen

Zhang

2007

Cardiovascular Drug Reviews

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Endothelial activation and dysfunction induced by oxidized modified low-density lipoprotein (ox-LDL) is one of the key steps in the initiation of atherosclerosis. Recent studies have shown that a new lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mediates the recognition and internalization of ox-LDL. LOX-1 is the main receptor for ox-LDL and may play an important role in the pathogenesis of hypertension, diabetes, and, especially, of atherosclerosis. The potential role of LOX-1 in the pathogenesis of atherosclerosis includes: endocytosis of ox-LDL, expression co-location with atherosclerosis enhanced by atherosclerosis-related risk factors, elevated LOX-1 protein in cardiovascular disease, effects related to atherosclerosis and eliminated by antiatherosclerotic drugs. Identification and regulation of LOX-1 and understanding its signal transduction pathways might improve our insight toward the pathogenesis of atherosclerosis and provide a selective treatment approach. LOX-1 might be a potential and promising target for the development of novel antiatherosclerotic drugs. However, due to limited knowledge about LOX-1, there are still many questions to be answered.

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Section: The Effects Of Antiatherosclerotic Drugsmentioning

confidence: 99%

Lectin‐like Oxidized Low‐density Lipoprotein Receptor‐1, a New Promising Target for the Therapy of Atherosclerosis?

Chen

Zhang

2007

Cardiovascular Drug Reviews

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“…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)(10)(11).…”

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confidence: 92%

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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“…Whether CRP plays a causal role in cardiovascular disease is still debated, but it has been shown to have direct proinflammatory effects on vascular endothelial cells and leukocytes with a modulation of cytokine expression, nitric oxide signaling, inflammatory gene expression, and leukocyte adhesion (5,7,17,26,28). The Fc␥ receptors Fc␥RI, Fc␥RIIa, and Fc␥RIIb have been identified as CRP receptors on leukocytes, vascular smooth muscle cells, and endothelial cells (26), and this interaction has been shown to mediate several CRP-mediated inflammatory functions including endothelial nitric oxide synthase dysregulation, superoxide generation, and increased ICAM-1 and VCAM-1 expression (5, 6, 12, 21), lending credence for the contributory role of CRP in cardiovascular disease.The lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1) is the primary oxLDL receptor in endothelial cells (22), and polymorphisms of LOX-1 are associated with several cardiovascular conditions including atherosclerosis, acute myocardial infarction, hypertension, and coronary heart disease (15,19,23). The activation of cell surface-expressed LOX-1 on endothelial cells is tethered to downstream inflammatory signaling pathways including NF-B and MAPK, resulting in inflammatory gene expression, superoxide generation, endothelial nitric oxide synthase deficiency, and increased monocyte adhesion to endothelial cells (11), similar to that observed for CRP.…”

mentioning

confidence: 99%

CRP is a novel ligand for the oxidized LDL receptor LOX-1

Shih¹,

Zhang²,

Cao³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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C-reactive protein (CRP) is a risk factor for cardiovascular events and functions to amplify vascular inflammation through promoting endothelial dysfunction. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1) is the primary endothelial receptor for oxLDL, and both its expression and function are associated with vascular inflammation. As a scavenger receptor, LOX-1 is capable of binding to a variety of structurally unrelated ligands. Evidence is provided that demonstrates that CRP can act as a novel ligand for LOX-1. The direct interaction between these two proteins was demonstrated with purified protein in both ELISA and AlphaScreen assays. This interaction could be disrupted with known LOX-1 ligands, such as oxLDL and carrageenan. Moreover, the CRP interaction with cell surface-expressed LOX-1 was confirmed in cell-based immunofluorescent-binding studies. Mutagenesis studies demonstrated that the arginine residues forming the basic spine structure on the LOX-1 ligand-binding interface were dispensable for CRP binding, suggesting a novel ligand-binding mechanism for LOX-1, distinct from that used for oxLDL binding. The treatment of human endothelial cells with CRP led to the activation of proinflammatory genes including IL-8, ICAM-1, and VCAM-1. The inductions of these genes by CRP were LOX-1 dependent, as demonstrated by their attenuation in cells transfected with LOX-1 small-interfering RNA. Our study identifies and characterizes the direct interaction between LOX-1 and CRP and suggests that this interaction may mediate CRP-induced endothelial dysfunction.

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Lectin-like oxidized-LDL receptor-1 (LOX-1) polymorphisms influence cardiovascular events rate during statin treatment

Cited by 18 publications

References 36 publications

Lectin‐like Oxidized Low‐density Lipoprotein Receptor‐1, a New Promising Target for the Therapy of Atherosclerosis?

Lectin‐like Oxidized Low‐density Lipoprotein Receptor‐1, a New Promising Target for the Therapy of Atherosclerosis?

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

CRP is a novel ligand for the oxidized LDL receptor LOX-1

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