scholarly journals The LOX-1 Scavenger Receptor and Its Implications in the Treatment of Vascular Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
M. W Twigg ◽  
K. Freestone ◽  
S. Homer-Vanniasinkam ◽  
S. Ponnambalam
Keyword(s):  
Vascular Disease ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Transgenic Animal ◽  
Lymphoid Cells ◽  
Scavenger Receptors ◽  
Model Studies ◽  
Arterial Blood ◽  
Oxidised Low Density Lipoprotein

Cardiovascular disease is the leading cause of death. The disease is due to atherosclerosis which is characterized by lipid and fat accumulation in arterial blood vessel walls. A key causative event is the accumulation of oxidised low density lipoprotein particles within vascular cells, and this is mediated by scavenger receptors. One such molecule is the LOX-1 scavenger receptor that is expressed on endothelial, vascular smooth muscle, and lymphoid cells including macrophages. LOX-1 interaction with OxLDL particles stimulates atherosclerosis. LOX-1 mediates OxLDL endocytosis via a clathrin-independent internalization pathway. Transgenic animal model studies show that LOX-1 plays a significant role in atherosclerotic plaque initiation and progression. Administration of LOX-1 antibodies in cellular and animal models suggest that such intervention inhibits atherosclerosis. Antiatherogenic strategies that target LOX-1 function using gene therapy or small molecule inhibitors would be new ways to address the increasing incidence of vascular disease in many countries.

Abstract 170: Development of a Novel Protein Nanobody Detection System for Serum Soluble Lectin-like Oxidised Low Density Lipoprotein Receptor-1

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jonathan De Siqueira ◽  
Caroline Seiler ◽  
David A Russell ◽  
Darren Tomlinson ◽  
Shervanthi Homer-Vanniasinkam ◽  
...  
Keyword(s):  
Limit Of Detection ◽  
Vascular Endothelial Cells ◽  
Detection System ◽  
Low Density Lipoprotein ◽  
Sandwich Elisa ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Wide Range ◽  
Oxidised Low Density Lipoprotein

Introduction: The Lectin-like Oxidised Low Density Lipoprotein (OxLDL) Receptor 1 (LOX-1) is a scavenger receptor found on vascular endothelial cells. LOX-1 is proteolysed at the cell surface and its soluble fragments (sLOX-1) are shed into the extracellular space. Clinical studies have demonstrated a link between serum sLOX-1 concentration and cardiovascular disease. Current technologies for the detection of sLOX-1 rely on costly monoclonal antibodies. Adhirons are antibody mimetics which can be directed against a wide range of molecules. We aimed to investigate whether Adhirons isolated against human sLOX-1 could be used to measure its concentration in solution. Methods: BL21 Star DE3 Escheriae Coli underwent transformation with plasmids for 5 different cysteine-tagged Adhirons. Protein expression was induced and, following bacterial lysis, these were purified using nickel-agarose columns. The binding of Adhirons to the extracellular domain of immobilised, recombinant human LOX-1 was tested by modified direct enzyme linked immunosorbance assay (ELISA). Adhiron-based, sandwich ELISA and Chemiluminescence Enzyme Immunoassay (CLEIA) were developed to detect sLOX-1 in solution. The application of these techniques in the detection of LOX-1 in biological buffers was tested. Results: Direct ELISA demonstrated a limit of detection (LOD) of 5 nanograms per millilitre. A complimentary binding pair of Adhirons (H 1 capture, A 1 detection and vice versa ) was identified. Colorimetry-based ELISA using these Adhirons detected sLOX-1 in phosphate buffered saline at an LOD of 150 nanograms per millilitre. CLEIA enabled a detection limit of 50 nanograms per millilitre, these results were reproduced in the presence of protein blockers (Bovine Serum Albumin, Casein). Conclusion: These experiments demonstrate proof of concept for the use of Adhirons as a viable platform for the detection of sLOX-1 in solution. Further refinement and optimisation is needed for the detection sLOX-1 levels in human blood samples (500 - 3000 picogram per millilitre concentration) in order to relate these to human disease.

scholarly journals Platelet CD36 signaling through ERK5 promotes caspase-dependent procoagulant activity and fibrin deposition in vivo

2018 ◽  
Vol 2 (21) ◽  
pp. 2848-2861 ◽  
Author(s):  
Moua Yang ◽  
Andaleb Kholmukhamedov ◽  
Marie L. Schulte ◽  
Brian C. Cooley ◽  
Na’il O. Scoggins ◽  
...  
Keyword(s):  
Platelet Reactivity ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Signaling Molecules ◽  
Chow Diet ◽  
Glycoprotein Vi ◽  
Platelet Signaling ◽  
Clinically Significant

Abstract Dyslipidemia is a risk factor for clinically significant thrombotic events. In this condition, scavenger receptor CD36 potentiates platelet reactivity through recognition of circulating oxidized lipids. CD36 promotes thrombosis by activating redox-sensitive signaling molecules, such as the MAPK extracellular signal-regulated kinase 5 (ERK5). However, the events downstream of platelet ERK5 are not clear. In this study, we report that oxidized low-density lipoprotein (oxLDL) promotes exposure of procoagulant phosphatidylserine (PSer) on platelet surfaces. Studies using pharmacologic inhibitors indicate that oxLDL-CD36 interaction–induced PSer exposure requires apoptotic caspases in addition to the downstream CD36-signaling molecules Src kinases, hydrogen peroxide, and ERK5. Caspases promote PSer exposure and, subsequently, recruitment of the prothrombinase complex, resulting in the generation of fibrin from the activation of thrombin. Caspase activity was observed when platelets were stimulated with oxLDL. This was prevented by inhibiting CD36 and ERK5. Furthermore, oxLDL potentiates convulxin/glycoprotein VI–mediated fibrin formation by platelets, which was prevented when CD36, ERK5, and caspases were inhibited. Using 2 in vivo arterial thrombosis models in apoE-null hyperlipidemic mice demonstrated enhanced arterial fibrin accumulation upon vessel injury. Importantly, absence of ERK5 in platelets or mice lacking CD36 displayed decreased fibrin accumulation in high-fat diet–fed conditions comparable to that seen in chow diet–fed animals. These findings suggest that platelet signaling through CD36 and ERK5 induces a procoagulant phenotype in the hyperlipidemic environment by enhancing caspase-mediated PSer exposure.

scholarly journals Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3468-3478 ◽  
Author(s):  
Adoración Venceslá ◽  
María Ángeles Corral-Rodríguez ◽  
Manel Baena ◽  
Mónica Cornet ◽  
Montserrat Domènech ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Missense Mutations ◽  
Factor X ◽  
Novel Mutations ◽  
Large Deletions ◽  
Function Relationship ◽  
The Impact

Abstract Hemophilia A (HA) is an X-linked bleeding disorder caused by a wide variety of mutations in the factor 8 (F8) gene, leading to absent or deficient factor VIII (FVIII). We analyzed the F8 gene of 267 unrelated Spanish patients with HA. After excluding patients with the common intron-1 and intron-22 inversions and large deletions, we detected 137 individuals with small mutations, 31 of which had not been reported previously. Eleven of these were nonsense, frameshift, and splicing mutations, whereas 20 were missense changes. We assessed the impact of the 20 substitutions based on currently available information about FV and FVIII structure and function relationship, including previously reported results of replacements at these and topologically equivalent positions. Although most changes are likely to cause gross structural perturbations and concomitant cofactor instability, p.Ala375Ser is predicted to affect cofactor activation. Finally, 3 further mutations (p.Pro64Arg, p.Gly494Val, and p.Asp2267Gly) appear to affect cofactor interactions with its carrier protein, von Willebrand factor, with the scavenger receptor low-density lipoprotein receptor–related protein (LRP), and/or with the substrate of the FVIIIapi•FIXa (Xase) complex, factor X. Characterization of these novel mutations is important for adequate genetic counseling in HA families, but also contributes to a better understanding of FVIII structure-function relationship.

scholarly journals CXCL16 Is Expressed in Podocytes and Acts as a Scavenger Receptor for Oxidized Low-Density Lipoprotein

2009 ◽  
Vol 174 (6) ◽  
pp. 2061-2072 ◽  
Author(s):  
Paul Gutwein ◽  
Mohamed Sadek Abdel-Bakky ◽  
Anja Schramme ◽  
Kai Doberstein ◽  
Nicole Kämpfer-Kolb ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein

Antibodies against Oxidised Low-density Lipoprotein in Juvenile Chronic Arthritis

1995 ◽  
Vol 24 (4) ◽  
pp. 209-211 ◽  
Author(s):  
A. Savolainen ◽  
R. von Essen ◽  
J. Leikola ◽  
G. Alfthan ◽  
O. Vaarala ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Juvenile Chronic Arthritis ◽  
Chronic Arthritis ◽  
Low Density ◽  
Oxidised Low Density Lipoprotein
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