Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease

2020 ◽  
Author(s):  
Alexander Akhmedov ◽  
Tatsuya Sawamura ◽  
Chu-Huang Chen ◽  
Simon Kraler ◽  
Daria Vdovenko ◽  
...  
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Basic Research ◽  
Plaque Formation ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Atheromatous Plaques

Abstract Cardiovascular diseases (CVDs), specifically lipid-driven atherosclerotic CVDs, remain the number one cause of death worldwide. The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), a scavenger receptor that promotes endothelial dysfunction by inducing pro-atherogenic signalling and plaque formation via the endothelial uptake of oxidized LDL (oxLDL) and electronegative LDL, contributes to the initiation, progression, and destabilization of atheromatous plaques, eventually leading to the development of myocardial infarction and certain forms of stroke. In addition to its expression in endothelial cells, LOX-1 is expressed in macrophages, cardiomyocytes, fibroblasts, dendritic cells, lymphocytes, and neutrophils, further implicating this receptor in multiple aspects of atherosclerotic plaque formation. LOX-1 holds promise as a novel diagnostic and therapeutic target for certain CVDs; therefore, understanding the molecular structure and function of LOX-1 is of critical importance. In this review, we highlight the latest scientific findings related to LOX-1, its ligands, and their roles in the broad spectrum of CVDs. We describe recent findings from basic research, delineate their translational value, and discuss the potential of LOX-1 as a novel target for the prevention, diagnosis, and treatment of related CVDs.

scholarly journals Identification of the lectin-like receptor for oxidized low-density lipoprotein in human macrophages and its potential role as a scavenger receptor

1998 ◽  
Vol 334 (1) ◽  
pp. 9-13 ◽  
Author(s):  
Hiroshi YOSHIDA ◽  
Nonna KONDRATENKO ◽  
Simone GREEN ◽  
Daniel STEINBERG ◽  
Oswald QUEHENBERGER
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Human Monocyte ◽  
Binding Activity ◽  
Low Density ◽  
Blood Monocytes ◽  
Oxidized Low Density Lipoprotein

A new receptor for oxidized low-density lipoprotein (LDL), lectin-like oxidized LDL receptor-1 (LOX-1), has recently been cloned from bovine endothelial cells and human lung. A limited tissue-distribution study suggested that the protein was mainly produced by the vascular endothelium. In the present study we demonstrate that LOX-1 is also expressed in macrophages, where it may function as a scavenger receptor. LOX-1 was not detected in undifferentiated THP-1 cells or in freshly isolated human blood monocytes. However, mature human monocyte-derived macrophages and differentiated THP-1 cells showed high levels of LOX-1 transcripts. Consistent with these results, immunofluorescence staining and FACS analysis demonstrated that LOX-1 protein is expressed on the plasma membrane of macrophages. Western-blot analysis of membranes from macrophages (but not those from monocytes) identified a single band, with an apparent molecular mass of about 40 kDa, that displayed oxidized LDL-binding activity. These results suggest that differentiation induces the expression of LOX-1 in macrophages, where it may play a role as a scavenger receptor and/or a receptor for oxidized LDL.

Identification of 4-hydroxy-2-nonenal–histidine adducts that serve as ligands for human lectin-like oxidized LDL receptor-1

2012 ◽  
Vol 442 (1) ◽  
pp. 171-180 ◽  
Author(s):  
Miyuki Kumano-Kuramochi ◽  
Yuuki Shimozu ◽  
Chika Wakita ◽  
Mayumi Ohnishi-Kameyama ◽  
Takahiro Shibata ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Chinese Hamster Ovary Cells ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Chinese Hamster ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Dependent Manner ◽  
Oxidized Low Density Lipoprotein

LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) is an endothelial scavenger receptor that is important for the uptake of OxLDL (oxidized low-density lipoprotein) and contributes to the pathogenesis of atherosclerosis. However, the precise structural motifs of OxLDL that are recognized by LOX-1 are unknown. In the present study, we have identified products of lipid peroxidation of OxLDL that serve as ligands for LOX-1. We used CHO (Chinese-hamster ovary) cells that stably express LOX-1 to evaluate the ability of BSA modified by lipid peroxidation to compete with AcLDL (acetylated low-density lipoprotein). We found that HNE (4-hydroxy-2-nonenal)-modified proteins most potently inhibited the uptake of AcLDL. On the basis of the findings that HNE-modified BSA and oxidation of LDL resulted in the formation of HNE–histidine Michael adducts, we examined whether the HNE–histidine adducts could serve as ligands for LOX-1. The authentic HNE–histidine adduct inhibited the uptake of AcLDL in a dose-dependent manner. Furthermore, we found the interaction of LOX-1 with the HNE–histidine adduct to have a dissociation constant of 1.22×10−8 M using a surface plasmon resonance assay. Finally, we showed that the HNE–histidine adduct stimulated the formation of reactive oxygen species and activated extracellular-signal-regulated kinase 1/2 and NF-κB (nuclear factor κB) in HAECs (human aortic endothelial cells); these signals initiate endothelial dysfunction and lead to atherosclerosis. The present study provides intriguing insights into the molecular details of LOX-1 recognition of OxLDL.

Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing the oxidized LDL receptor

2013 ◽  
Vol 305 (2) ◽  
pp. H155-H162 ◽  
Author(s):  
Sayoko Ogura ◽  
Tatsuo Shimosawa ◽  
ShengYu Mu ◽  
Takashi Sonobe ◽  
Fumiko Kawakami-Mori ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Ros Generation ◽  
Low Density ◽  
Ros Production ◽  
Oxidized Low Density Lipoprotein

Chronic hypoxia is one of the main causes of pulmonary hypertension (PH) associated with ROS production. Lectin-like oxidized low-density lipoprotein receptor (LOX)-1 is known to be an endothelial receptor of oxidized low-density lipoprotein, which is assumed to play a role in the initiation of ROS generation. We investigated the role of LOX-1 and ROS generation in PH and vascular remodeling in LOX-1 transgenic (TG) mice. We maintained 8- to 10-wk-old male LOX-1 TG mice and wild-type (WT) mice in normoxia (room air) or hypoxia (10% O2 chambers) for 3 wk. Right ventricular (RV) systolic pressure (RVSP) was comparable between the two groups under normoxic conditions; however, chronic hypoxia significantly increased RVSP and RV hypertrophy in LOX-1 TG mice compared with WT mice. Medial wall thickness of the pulmonary arteries was significantly greater in LOX-1 TG mice than in WT mice. Furthermore, hypoxia enhanced ROS production and nitrotyrosine expression in LOX-1 TG mice, supporting the observed pathological changes. Administration of the NADPH oxidase inhibitor apocynin caused a significant reduction in PH and vascular remodeling in LOX-1 TG mice. Our results suggest that LOX-1-ROS generation induces the development and progression of PH.

scholarly journals Oxidized LDL but not angiotensin II induces the interaction between LOX-1 and AT1 receptors

2020 ◽  
Author(s):  
Li Lin ◽  
Ning Zhou ◽  
Le Kang ◽  
Qi Wang ◽  
Jian Wu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Direct Interaction ◽  
Cardiomyocyte Hypertrophy ◽  
Oxidized Low Density Lipoprotein ◽  
Protein Activation

Oxidized low-density lipoprotein (Ox-LDL) can induce cardiac hypertrophy, but the mechanism is still unclear. Here we elucidate the role of angiotensin II (AngII) receptor (AT1-R) in Ox-LDL-induced cardiomycyte hypertrophy. Inhibition of Ox-LDL receptor LOX-1 and AT1-R rather than AngII abolished Ox-LDL-induced hypertrophic responses. Similar results were obtained from the heart of mice lacking endogenous Ang II and their cardiomyocytes. Ox-LDL but not AngII induced binding of LOX-1 to AT1-R, and the inhibition of LOX-1 or AT1-R rather than AngII abolished the association of these two receptors. Ox-LDL-induced ERKs phosphorylation in LOX-1 and AT1-R-overexpression cells and the binding of both receptors were suppressed by the mutants of LOX-1 (Lys266Ala/Lys267Ala) or AT1-R (Glu257Ala), however, the AT1-R mutant lacking Gq protein-coupling ability only abolished the ERKs phosphorylation. The phosphorylation of ERKs induced by Ox-LDL in LOX-1 and AT1-R-overexpression cells was abrogated by Gq protein inhibitor but not by Jak2, Rac1 and RhoA inhibitors. Therefore, the direct interaction between LOX-1 and AT1-R and the downstream Gq protein activation are important mechanisms for Ox-LDL- but not AngII-induced cardiomyocyte hypertrophy

Influence of gender on vasomotor effects of oxidized low-density lipoprotein in porcine coronary arteries

1997 ◽  
Vol 272 (6) ◽  
pp. H2577-H2583 ◽  
Author(s):  
D. A. Cox ◽  
M. L. Cohen
Keyword(s):  
Coronary Arteries ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Male And Female ◽  
No Release ◽  
Contraction And Relaxation ◽  
Coronary Endothelium

This study compared 5-hydroxytryptamine (5-HT)-induced contraction and relaxation in coronary arteries from male and female pigs and compared the vasomotor effects of the atherosclerotic lipoprotein, oxidized low-density lipoprotein (LDL), in these tissues. 5-HT-induced contraction and endothelium-dependent relaxation were similar, as was sodium nitroprusside-induced relaxation, in coronary arteries from male and female pigs. These data suggest that there were no gender-related differences in 5-HT-induced contraction or 5-HT-mediated nitric oxide (NO) release from the coronary endothelium. In contrast, oxidized LDL (100 micrograms/ml) enhanced 5-HT-induced contraction to a greater extent in coronary arteries from male versus female pigs. Because oxidized LDL inhibited 5-HT-induced relaxation similarly in arteries from male and female animals, a greater effect of oxidized LDL on agonist-induced NO release in tissues from male pigs cannot explain the greater effect on 5-HT-induced contraction. Oxidized LDL contracted coronary arteries from males with a greater force than arteries from females when measured from baseline tone, suggesting that oxidized LDL inhibited basal NO release to a greater extent in coronary arteries from male pigs compared with females, an effect that may have participated in the greater enhancement of 5-HT-induced contraction that occurred in arteries from male pigs. These gender-related differences in the vasomotor effects of oxidized LDL may play an important role in the lesser incidence of cardiovascular disease in premenopausal females than in males and may provide insight into the cardioprotective effect of estrogen.

scholarly journals Treatment of macrophages with oxidized low-density lipoprotein increases their intracellular glutathione content

1991 ◽  
Vol 278 (2) ◽  
pp. 429-434 ◽  
Author(s):  
V M Darley-Usmar ◽  
A Severn ◽  
V J O'Leary ◽  
M Rogers
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Human Monocyte ◽  
Cell Types ◽  
Oxidative Modification ◽  
Glutathione Depletion ◽  
Lipid Phase ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein

Macrophages derived from the human monocyte cell line THP-1 or isolated from the peritoneum of C3H/HEJ mice were incubated with oxidized low-density lipoprotein (LDL) and the total glutathione content (oxidized plus reduced) was measured. An initial depletion of glutathione was followed by an increase, such that after a period of 24 h the glutathione content has approximately doubled. This response required the oxidation of the lipid phase of the LDL molecule, since both native LDL and acetylated LDL had little effect on glutathione levels. The response of the cells to oxidized LDL was dependent on the extent of oxidative modification of the protein. It was also found that 4-hydroxynonenal had a similar effect on THP-1 cells, and we suggest that this or other aldehydes present in oxidized LDL causes the induction of glutathione synthesis in response to an initial oxidative stress and consequent glutathione depletion. In addition, we found that both cell types possess transferases and peroxidases capable of detoxifying aldehydes and peroxides. However, treatment of cells with oxidized LDL or 4-hydroxynonenal for a period of 24 h had no effect on the activities of these enzymes.

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