Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1) in Atherogenesis

doi:10.1016/S1050-1738(01)00079-2

Trends in Cardiovascular Medicine

Volume 11, Issue 1, January 2001, Pages 22-25

https://doi.org/10.1016/S1050-1738(01)00079-2 Get rights and content

Abstract

Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) is a type-II membrane protein belonging to the C-type lectin family molecules, which can act as a cell surface endocytosis receptor for atherogenic oxidized LDL (Ox-LDL). LOX-1 is synthesized as a 40 kDa precursor protein with N-linked high mannose-type carbohydrate, which is further glycosylated and processed into a 50 kDa mature form. LOX-1 expression is not constitutive but can be induced by proinflammatory, oxidative, and mechanical stimuli. In addition to endothelial cells, macrophages and activated vascular smooth muscle cells express LOX-1. In vivo, endothelial cells covering early atherosclerotic lesions and macrophages and smooth muscle cells accumulated in the intima of advanced atherosclerotic plaques express LOX-1. LOX-1 is cleaved at membrane proximal extracellular domain by some protease activities and released from the cell surface. Measurement of soluble LOX-1 in vivo may provide novel diagnostic strategy for the evaluation and prediction of atherosclerosis and vascular diseases.

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The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for binding and uptake of oxidized low-density lipoprotein (oxLDL) in endothelial cells. LOX-1 is also expressed in macrophages, smooth muscle cells and platelets. Following internalization of oxLDL, LOX-1 initiates a vicious cycle from activation of pro-inflammatory signaling pathways, thus promoting an increased reactive oxygen species formation and secretion of pro-inflammatory cytokines. LOX-1 plays a pivotal role in the development of endothelial dysfunction, foam cell and advanced lesions formation as well as in myocardial ischemia. Furthermore, it is known that LOX-1 plays a pivotal role in mitochondrial DNA damage, vascular cell apoptosis, and autophagy. A large number of studies provide evidence of a LOX-1′s role in endothelial dysfunction, hypertension, diabetes, and obesity. In addition, novel insights into LOX-1 ligands and the activated signaling pathways have been gained. Recent studies have shown an interaction of LOX-1 with microRNA's, thus providing novel tools to regulate LOX-1 function. Because LOX-1 is increased in atherosclerotic plaques and contributes to endothelial dysfunction, several compounds were tested in vivo and in vitro to modulate the LOX-1 expression in therapeutic approaches.
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Hyaluronic-acid (HA)-coated LOX-1-specific siRNA-condensed cell-penetrating peptide (CPP) nanocomplexes (NCs) were developed for targeted gene delivery to macrophages and suppression of lipid accumulation. The HA coating facilitated the accumulation of nanoparticles at leaky endothelium overexpressing CD44 receptors and was further degraded by hyaluronidase (HAase) intraplaques for exposing the naked CPP NCs and achieving the ultimate location into macrophages. The surface coating of HA was verified by the increased particle size, inverted zeta potential, and TEM images. The targeting mechanism was studied on the established injured endothelium–macrophage coculture system, which revealed that modification of higher molecular weight HA and higher HA coating density on NCs, termed as NPs-3, improved the intracellular uptake of nanoparticles by macrophages. Macrophages internalized NCs via caveolae-mediated endocytosis pathway. Moreover, NPs-3 exhibited better cellular drug efficacy in preventing macrophage-derived foam cell formation than other preparations. Compared with NCs, HA decoration showed enhanced atherosclerotic-lesion-targeting efficiency, proven by results from ex vivo imaging. Furthermore, atheroprotective efficacy study in apoE-deficient mice showed that NPs-3 had the best potent efficacy, which was demonstrated by the fewest atherosclerotic lesions sizes and lipid accumulation, the lowest macrophage infiltration, and the lowest expression of monocyte chemoattractant protein-1 (MCP-1), respectively. Collectively, the HA-coated CPP NCs were promising nanocarriers for efficient macrophage-targeted gene delivery and antiatherogenic therapy.
LOX-1 receptor: A potential link in atherosclerosis and cancer
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Citation Excerpt :
LOX-1 contributes of endothelial cell dysfunction, apoptosis and the formation of plaque because it induces inflammatory cytokines with subsequent adhesion molecules and monocyte recruitment [23]. LOX-1 expression is very low in physiological condition and it is upregulated in vascular endothelium of human atherosclerosis [27–29], hypertension [78] and myocardial ischemia [30]. Besides ox-LDL, further ligands binds LOX-1, such as 15-lipoxygenase modified HDL [31] and glycoxidized LDL [32].
Altered production of reactive oxygen species (ROS), causing lipid peroxidation and DNA damage, contributes to the progression of atherosclerosis and cancer. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a lectin-like receptor for oxidized low-density lipoproteins (ox-LDL) primarily expressed in endothelial cells and vasculature-rich organs. LOX-1 receptors is a marker for atherosclerosis, and once activated by ox-LDL or other ligands, stimulates the expression of adhesion molecules, pro-inflammatory signaling pathways and proangiogenic proteins, including NF-kB and VEGF, in vascular endothelial cells and macrophages. Several different types of cancer reported LOX-1 gene upregulation, and numerous interplays exist concerning LOX-1 in atherosclerosis, metabolic diseases and cancer. One of them involves NF-kB, an oncogenic protein that regulates the transcription of several inflammatory genes response. In a model of cellular transformation, the MCF10A ER-Src, inhibition of LOX-1 gene reduces NF-kB activation and the inflammatory and hypoxia pathways, suggesting a mechanistic connection between cellular transformation and atherosclerosis. The remodeling proteins MMP-2 and MMP-9 have been found increased in angiogenesis in atherosclerotic plaque and also in human prostate cancer cells.
In this review, we outlined the role of LOX-1 in atherogenesis and tumorigenesis as a potential link in these diseases, suggesting that LOX-1 inhibition could represent a promising strategy in the treatment of atherosclerosis and tumors.
Dual signaling evoked by oxidized LDLs in vascular cells
2017, Free Radical Biology and Medicine
Citation Excerpt :
This effect is reversed by an anti-LOX-1 antibody and is not observed in LOX-1 KO mice [113]. LOX-1 is inducible by oxLDLs, proinflammatory cytokines, TGFβ, angiotensin II, bacterial endotoxin, apoptotic cells or shear stress [114]. ROS evoked by proinflammatory cytokines or oxLDLs exert a positive feedback on LOX-1 expression, thereby maintaining or increasing oxLDL uptake, ROS production and inflammation [115].
The oxidative theory of atherosclerosis relies on the modification of low density lipoproteins (LDLs) in the vascular wall by reactive oxygen species. Modified LDLs, such as oxidized LDLs, are thought to participate in the formation of early atherosclerotic lesions (accumulation of foam cells and fatty streaks), whereas their role in advanced lesions and atherothrombotic events is more debated, because antioxidant supplementation failed to prevent coronary disease events and mortality in intervention randomized trials.
As oxidized LDLs and oxidized lipids are present in atherosclerotic lesions and are able to trigger cell signaling on cultured vascular cells and macrophages, it has been proposed that they could play a role in atherogenesis and atherosclerotic vascular remodeling.
Oxidized LDLs exhibit dual biological effects, which are dependent on extent of lipid peroxidation, nature of oxidized lipids (oxidized phospholipids, oxysterols, malondialdehyde, α,β-unsaturated hydroxyalkenals), concentration of oxidized LDLs and uptake by scavenger receptors (e.g. CD36, LOX-1, SRA) that signal through different transduction pathways. Moderate concentrations of mildly oxidized LDLs are proinflammatory and trigger cell migration and proliferation, whereas higher concentrations induce cell growth arrest and apoptosis. The balance between survival and apoptotic responses evoked by oxidized LDLs depends on cellular systems that regulate the cell fate, such as ceramide/sphingosine-1-phosphate rheostat, endoplasmic reticulum stress, autophagy and expression of pro/antiapoptotic proteins. In vivo, the intimal concentration of oxidized LDLs depends on the influx (hypercholesterolemia, endothelial permeability), residence time and lipid composition of LDLs, oxidative stress intensity, induction of defense mechanisms (antioxidant systems, heat shock proteins). As a consequence, the local cellular responses to oxidized LDLs may stimulate inflammatory or anti-inflammatory pathways, angiogenic or antiangiogenic responses, survival or apoptosis, thereby contributing to plaque growth, instability, complication (intraplaque hemorrhage, proteolysis, calcification, apoptosis) and rupture. Finally, these dual properties suggest that oxLDLs could be implicated at each step of atherosclerosis development, from early fatty streaks to advanced lesions, depending on the nature and concentration of their oxidized lipid content.
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We investigated how docosahexaenoic acid (DHA) regulated tumor necrosis factor-alpha (TNF-α)-induced senescence and dysfunction in endothelial cells (EC). We used RT-PCR to examine the expression of several genes related to senescence and dysfunction in EC. TNF-α-induced p21 protein levels were investigated by Western blot (WB) and fluorescence antibody techniques. TNF-α induced the senescence marker β-galactosidase and the expression of several senescence and endothelial dysfunction-related genes, e.g., CDKN1A, SHC1 and GLB1. DHA attenuated TNF-α-induced senescence-related gene expression and p21 protein expression. DHA attenuated TNF-α-induced gene expression related to dysfunction of EC, such as plasminogen activator inhibitor 1 (SERPINE1), lectin-like oxidized low-density lipoprotein receptor-1 (OLR1), thromboxane A2 receptor (TXA2R) and p38 MAPK (MAPK14). DHA reversed the TNF-α-mediated reduction of endothelial nitric oxide synthase (NOS3) gene expression. TNF-α-mediated upregulation of these genes was inhibited by allopurinol and apocynin. These results indicated that DHA regulated the expression of several genes that are associated with senescence and dysfunction of EC.

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Brief reviewLectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1) in Atherogenesis

Abstract

FEBS Lett

J Mol Cell Cardiol

J Biol Chem

J Biol Chem

Biochim Biophys Acta

Biochem Biophys Res Commun

FEBS Lett

Biochem Biophys Res Commun

Expression cloning of SR-BI, a CD36-related class B scavenger receptor

J Biol Chem

Expression cloning of a novel scavenger receptor from human endothelial cells

J Biol Chem

Structure and chromosomal assignment of the human lectin-like oxidized low-density-lipoprotein receptor-1 (Lox-1) gene

Biochem J

Receptors for oxidized low-density lipoprotein on elicited mouse peritoneal macrophages can recognize both the modified lipid moieties and the modified protein moietiesimplications with respect to macrophage recognition of apoptotic cells

Proc Natl Acad Sci USA

Contrary effects of lightly and strongly oxidized LDL with potent promotion of growth versus apoptosis on arterial smooth muscle cells, macrophages, and fibroblasts

Arterioscler Thromb Vasc Biol

Increased expression of lectin-like oxidized low density lipoprotein receptor-1 in initial atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits

Arterioscler Thromb Vasc Biol

Oxidized low-density lipoprotein binding to LOX-1 in endothelial cells induces the activation of NF-kB through an increased production of intracellular reactive oxygen species

J Biol Chem

CD36 is a receptor for oxidized low density lipoprotein

J Biol Chem

A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1

Proc Natl Acad Sci USA

Expression of lectin-like oxidized low density lipoprotein receptor-1 in human atherosclerotic lesions

Circulation

LOX-1, a possible clue to the missing link between hypertension and atherogenesis

Circ Res

Type I macrophage scavenger receptor contains alpha-helical collagen-like coiled coils

Nature

Brief review
Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 (LOX-1) in Atherogenesis