Atherosclerosis

2007

DOI: 10.1016/j.atherosclerosis.2006.11.031

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Lectin-like oxidized LDL receptor-1 (LOX-1) expression is associated with atherosclerotic plaque instability—analysis in hypercholesterolemic rabbits

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Cited by 79 publications

(57 citation statements)

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“…A monoclonal antibody for rabbit LOX-1 (mouse IgG) was established by a standard hybridoma technique. 16) Its specificity was confirmed in CHO cells stably expressing rabbit LOX-1 (data not shown). A monoclonal antibody for rabbit TF (mouse IgG) was obtained from American Diagnostica (Stanford, CA, U.S.A.).…”

Section: Methodsmentioning

confidence: 75%

“…In this context, we recently demonstrated that LOX-1 expression is related to MMP-9 expression and morphological plaque vulnerability using a rabbit model of spontaneous atherosclerosis, 16) 17,18) Thus, in the present study, we compared LOX-1 expression with TF expression and apoptosis in atherosclerotic lesions of WHHLMI rabbits, in order to further characterize the roles of LOX-1 to the plaque vulnerability and thrombus formation in vivo.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Prominent Lectin-Like Oxidized Low Density Lipoprotein (LDL) Receptor-1 (LOX-1) Expression in Atherosclerotic Lesions Is Associated with Tissue Factor Expression and Apoptosis in Hypercholesterolemic Rabbits

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et al. 2008

Biological & Pharmaceutical Bulletin

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Rupture or erosion of vulnerable atherosclerotic plaques and the subsequent formation of occlusive thrombi are currently recognized as the primary causes of acute coronary syndrome and stroke. 1) Vulnerability of atherosclerotic plaques, rather than severity of luminal stenosis, has been suggested to be the most important determinant for the onset of acute coronary syndrome.2) Accordingly, it is of great importance to determine causative factors in the destabilization of atherosclerotic plaques and in the thrombus formation, which should help develop new therapeutic and diagnostic (imaging) agents of atherosclerosis, leading to the establishment of novel therapeutic strategies for preventing acute coronary syndromes and stroke.To date, enhanced proinflammatory responses and the expression of matrix metalloproteinases (MMPs) have been suggested to play important roles in the destabilization of atherosclerotic plaques. Apoptosis and prothrombotic factors in atherosclerotic plaques have also been reported to be crucial factors for the plaque vulnerability and thrombus formation.3) Apoptosis of foam cells and macrophages contributes to the formation of an acellular (cell-poor) lipid core, 4) and the apoptosis of smooth muscle cells further weaken the fibrous cap by decreasing the synthesis of extracellular matrix proteins.5) Tissue factor (TF), a cofactor for plasma coagulation factor VIIa, which is localized in vascular cells and the lipid core within the atherosclerotic lesions, is an initiator of the coagulation cascade leading to thrombus formation after the plaque rupture in vivo. 3)Lectin-like oxidized low density lipoprotein (LDL) receptor-1 (LOX-1), a type II membrane glycoprotein belonging to the C-type lectin family, acts as a cell-surface receptor for oxidized LDL (Ox-LDL) and mediates several biological effects of Ox-LDL.6) Recent studies with cultured cells suggest that LOX-1 may play several important roles in destabilization of atherosclerotic plaques, inducing expression of adhesion molecules and chemokines for monocytes, 7) transformation of macrophages into foam cells, 8,9) apoptosis of smooth muscle cells 10,11) and the degradation of extracellular matrix proteins by induction of matrix metalloproteinases.12) Several studies with cultured cells also showed that Ox-LDL, through LOX-1, also triggers the CD40/CD40L signaling pathway, 13,14) which then induce TF expression. 15) These biological effects mediated by Ox-LDL-LOX-1 interactions may enlarge the lipid core, weaken the fibromuscular cap, and induce proinflammatory responses, resulting in destabilization of the atherosclerotic plaques and thrombus formation.The actual contribution of LOX-1 to the plaque vulnerability and thrombus formation in vivo, however, remains unclear. In this context, we recently demonstrated that LOX-1 expression is related to MMP-9 expression and morphological plaque vulnerability using a rabbit model of spontaneous atherosclerosis, 16) myocardial infarction-prone Watanabe her- Background: Despite increasing in vitro e...

“…A monoclonal antibody for rabbit LOX-1 (mouse IgG) was established by a standard hybridoma technique. 16) Its specificity was confirmed in CHO cells stably expressing rabbit LOX-1 (data not shown). A monoclonal antibody for rabbit TF (mouse IgG) was obtained from American Diagnostica (Stanford, CA, U.S.A.).…”

Section: Methodsmentioning

confidence: 75%

“…In this context, we recently demonstrated that LOX-1 expression is related to MMP-9 expression and morphological plaque vulnerability using a rabbit model of spontaneous atherosclerosis, 16) 17,18) Thus, in the present study, we compared LOX-1 expression with TF expression and apoptosis in atherosclerotic lesions of WHHLMI rabbits, in order to further characterize the roles of LOX-1 to the plaque vulnerability and thrombus formation in vivo.…”

mentioning

confidence: 99%

Prominent Lectin-Like Oxidized Low Density Lipoprotein (LDL) Receptor-1 (LOX-1) Expression in Atherosclerotic Lesions Is Associated with Tissue Factor Expression and Apoptosis in Hypercholesterolemic Rabbits

¹

,

²

,

³

et al. 2008

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

Rupture or erosion of vulnerable atherosclerotic plaques and the subsequent formation of occlusive thrombi are currently recognized as the primary causes of acute coronary syndrome and stroke. 1) Vulnerability of atherosclerotic plaques, rather than severity of luminal stenosis, has been suggested to be the most important determinant for the onset of acute coronary syndrome.2) Accordingly, it is of great importance to determine causative factors in the destabilization of atherosclerotic plaques and in the thrombus formation, which should help develop new therapeutic and diagnostic (imaging) agents of atherosclerosis, leading to the establishment of novel therapeutic strategies for preventing acute coronary syndromes and stroke.To date, enhanced proinflammatory responses and the expression of matrix metalloproteinases (MMPs) have been suggested to play important roles in the destabilization of atherosclerotic plaques. Apoptosis and prothrombotic factors in atherosclerotic plaques have also been reported to be crucial factors for the plaque vulnerability and thrombus formation.3) Apoptosis of foam cells and macrophages contributes to the formation of an acellular (cell-poor) lipid core, 4) and the apoptosis of smooth muscle cells further weaken the fibrous cap by decreasing the synthesis of extracellular matrix proteins.5) Tissue factor (TF), a cofactor for plasma coagulation factor VIIa, which is localized in vascular cells and the lipid core within the atherosclerotic lesions, is an initiator of the coagulation cascade leading to thrombus formation after the plaque rupture in vivo. 3)Lectin-like oxidized low density lipoprotein (LDL) receptor-1 (LOX-1), a type II membrane glycoprotein belonging to the C-type lectin family, acts as a cell-surface receptor for oxidized LDL (Ox-LDL) and mediates several biological effects of Ox-LDL.6) Recent studies with cultured cells suggest that LOX-1 may play several important roles in destabilization of atherosclerotic plaques, inducing expression of adhesion molecules and chemokines for monocytes, 7) transformation of macrophages into foam cells, 8,9) apoptosis of smooth muscle cells 10,11) and the degradation of extracellular matrix proteins by induction of matrix metalloproteinases.12) Several studies with cultured cells also showed that Ox-LDL, through LOX-1, also triggers the CD40/CD40L signaling pathway, 13,14) which then induce TF expression. 15) These biological effects mediated by Ox-LDL-LOX-1 interactions may enlarge the lipid core, weaken the fibromuscular cap, and induce proinflammatory responses, resulting in destabilization of the atherosclerotic plaques and thrombus formation.The actual contribution of LOX-1 to the plaque vulnerability and thrombus formation in vivo, however, remains unclear. In this context, we recently demonstrated that LOX-1 expression is related to MMP-9 expression and morphological plaque vulnerability using a rabbit model of spontaneous atherosclerosis, 16) myocardial infarction-prone Watanabe her- Background: Despite increasing in vitro e...

“…Through interactions with LOX1, oxLDL activates ECs and induces endothelial dysfunction and apoptosis (Mehta et al 2006). In this study, we found that LOX1 is highly expressed in primary HLSECs upon oxLDL stimulation, and the effect of oxLDL is dose-and time-dependent in vascular ECs (Li & Mehta 2000, Ishino et al 2007. Results from a previous study have indicated that LOX1 expression is increased in atherosclerotic plaques when compared with normal endothelial tissue (Ishino et al 2007), and Lox1 knockout mice exhibit markedly smaller atherosclerotic lesions (Mehta et al 2007), indicating that LOX1 plays an important role in HLSEC dysfunction.…”

Section: Discussionmentioning

confidence: 81%

oxLDL induces injury and defenestration of human liver sinusoidal endothelial cells via LOX1

Liu²,

Liu³

et al. 2014

Journal of Molecular Endocrinology

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Non-alcoholic fatty liver disease is associated with hepatic microangiopathy and liver inflammation caused by type 2 diabetes mellitus. Oxidised LDL (oxLDL) is involved in proinflammatory and cytotoxic events in various microcirculatory systems. The lectin-like oxLDL receptor 1 (LOX1) plays a crucial role in oxLDL-induced pathological transformation. However, the underlying mechanism of oxLDL's effects on liver microcirculation disturbances remains unclear. In this study, we investigated the effects of oxLDL on LOX1 (OLR1) expression and function, as well as on the fenestration features of human liver sinusoidal endothelial cells (HLSECs) in vitro. Primary HLSECs were obtained and cultured. The cells were treated with various concentrations of oxLDL (25, 50, 100 and 200 mg/ml), and the cytotoxicity and expression of LOX1 were examined. Furthermore, LOX1 knockdown was performed using siRNA technology, and the changes in intracellular reactive oxygen species (ROS), NFkB, p65, (p65), endothelin 1 (ET1 (EDN1)), eNOS (NOS3) and caveolin 1 (CAV1) levels were measured. Cells were treated with 100 mg/ml oxLDL, and the fenestra morphology was visualised using scanning electron microscopy. oxLDL significantly increased LOX1 expression at both the mRNA and protein levels in HLSECs in a dose-and time-dependent manner. oxLDL stimulation increased ROS generation and NFkB activation, upregulated ET1 and caveolin 1 expression, downregulated eNOS expression and reduced the fenestra diameter and porosity. All of these oxLDLmediated effects were inhibited after LOX1 knockdown. These results reveal a mechanism by which oxLDL stimulates the production of LOX1 through the ROS/NFkB signalling pathway and by which LOX1 mediates oxLDL-induced endothelial injury and the defenestration of HLSECs. Key Words" oxidised LDL " lectin-like oxLDL receptor 1 " endothelial injury " defenestration " human liver sinusoidal endothelial cells

“…Furthermore, LOX-1 expression was shown in the macrophage-rich lipid core area where MCP-1 expression and apoptotic events were prominent. These results indicate that enhanced LOX-1 expression was associated with histologically unstable atherosclerotic plaques, suggesting the involvement of LOX-1 in the destabilization of atherosclerotic plaques in vivo (Ishino et al 2007). …”

Section: The Effects Of Antiatherosclerotic Drugsmentioning

confidence: 92%

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

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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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