Abstract 832: The Farnesoid X Receptor (FXR) Antagonizes Oxidized LDL Receptor, LOX-1, Activation

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Douglas Harnish ◽  
Ashleigh Hahn ◽  
Helen Hartman ◽  
Christine Huard ◽  
Robert Martinez ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Function ◽  
Oxidized Ldl ◽  
Vascular Inflammation ◽  
Scavenger Receptor ◽  
Ldl Receptor ◽  
Nuclear Hormone Receptor ◽  
Western Diet ◽  
Farnesoid X Receptor ◽  
Chow Diet

The nuclear hormone receptor farnesoid X receptor (FXR) plays a critical role in the regulation of enterohepatic circulation and lipid homeostasis and may also positively impact vascular inflammation and endothelial function through the antagonism of oxidized LDL receptor, LOX-1, activation. LOX-1 is a endothelial membrane bound scavenger receptor that upon ligand binding stimulates NF-κB and MAPK pathways leading to adhesion molecule and inflammatory gene expression with subsequent nitric oxide inhibition. Since LOX-1 is activated by oxLDL, LOX-1 expression was monitored in LDLR −/− mice fed a western diet. Hepatic LOX-1 mRNA was significantly induced by 7 days on the western diet compared to chow fed controls. Moreover, this LOX-1 induction was dose dependently inhibited with increasing concentrations of a potent synthetic FXR ligand WAY-362450 (FXR-450; 1–30 mg/kg po) as were downstream LOX-1 dependent genes, VCAM-1 and ICAM-1. The regulation of LOX-1 was FXR-specific since another oxLDL hepatic scavenger receptor, CD36, expression was not affected by FXR-450. To determine whether this signaling pathway was active in other settings, the FXR mediated regulation of LOX-1 was studied in the diabetic mouse strain, KKAy. Both hepatic and renal LOX-1 expression was inhibited by 30 mg/kg FXR-450 after 7 days of dosing on a chow diet and resulted in the reduction of serum soluble LOX-1 levels as well. Renal gene profiling studies indicated that FXR-450 stimulated genes involved in nitric oxide production, including DDAH-1, ASS-1 and GTPCH that were all confirmed to be induced in the KKAy mouse model. Since the nitric oxide synthase antagonist ADMA stimulates LOX-1 expression, we postulated that the positive impact of FXR-450 was due to the decrease in local ADMA concentrations via DDAH-1, ASS-1 and GTPCH inductions. In support of this, ADMA mediated induction of LOX-1 was also inhibited by FXR-450 treatment. Therefore, these results identify a novel cross-talk between FXR and LOX-1 signaling pathways through their co-ordinate modulation of the nitric oxide pathway and suggest that FXR agonists may have a beneficial impact on vascular inflammation and endothelial function.

F(ab′)2 fragments of anti-oxidized LDL IgG attenuate vascular inflammation and atherogenesis in diabetic LDL receptor-deficient mice

2016 ◽  
Vol 173 ◽  
pp. 50-56 ◽  
Author(s):  
Yanchun Li ◽  
Zhongyang Lu ◽  
Yan Huang ◽  
Maria F. Lopes-Virella ◽  
Gabriel Virella
Keyword(s):  
Oxidized Ldl ◽  
Vascular Inflammation ◽  
Ldl Receptor ◽  
Deficient Mice

scholarly journals Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10–producing suppressive CD4+ T cells

2012 ◽  
Vol 209 (1) ◽  
pp. 109-121 ◽  
Author(s):  
Dapeng Li ◽  
Gabrielle Romain ◽  
Anne-Laure Flamar ◽  
Dorothée Duluc ◽  
Melissa Dullaers ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Oxidized Ldl ◽  
Scavenger Receptor ◽  
Ldl Receptor ◽  
Interleukin 10 ◽  
Protein Antigens ◽  
Host Immune Responses

Dendritic cells (DCs) can initiate and shape host immune responses toward either immunity or tolerance by their effects on antigen-specific CD4+ T cells. DC-asialoglycoprotein receptor (DC-ASGPR), a lectinlike receptor, is a known scavenger receptor. Here, we report that targeting antigens to human DCs via DC-ASGPR, but not lectin-like oxidized-LDL receptor, Dectin-1, or DC-specific ICAM-3–grabbing nonintegrin favors the generation of antigen-specific suppressive CD4+ T cells that produce interleukin 10 (IL-10). These findings apply to both self- and foreign antigens, as well as memory and naive CD4+ T cells. The generation of such IL-10–producing CD4+ T cells requires p38/extracellular signal-regulated kinase phosphorylation and IL-10 induction in DCs. We further demonstrate that immunization of nonhuman primates with antigens fused to anti–DC-ASGPR monoclonal antibody generates antigen-specific CD4+ T cells that produce IL-10 in vivo. This study provides a new strategy for the establishment of antigen-specific IL-10–producing suppressive T cells in vivo by targeting whole protein antigens to DCs via DC-ASGPR.

scholarly journals Modulation of Nitric Oxide Synthases by Oxidized LDLs: Role in Vascular Inflammation and Atherosclerosis Development

2019 ◽  
Vol 20 (13) ◽  
pp. 3294 ◽  
Author(s):  
Micaela Gliozzi ◽  
Miriam Scicchitano ◽  
Francesca Bosco ◽  
Vincenzo Musolino ◽  
Cristina Carresi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Vascular Inflammation ◽  
Scavenger Receptor ◽  
The Other ◽  
Pathophysiological Mechanism ◽  
Other Hand ◽  
Nfkb Activation ◽  
Significant Impairment ◽  
Atherosclerosis Development

The maintenance of physiological levels of nitric oxide (NO) produced by eNOS represents a key element for vascular endothelial homeostasis. On the other hand, NO overproduction, due to the activation of iNOS under different stress conditions, leads to endothelial dysfunction and, in the late stages, to the development of atherosclerosis. Oxidized LDLs (oxLDLs) represent the major candidates to trigger biomolecular processes accompanying endothelial dysfunction and vascular inflammation leading to atherosclerosis, though the pathophysiological mechanism still remains to be elucidated. Here, we summarize recent evidence suggesting that oxLDLs produce significant impairment in the modulation of the eNOS/iNOS machinery, downregulating eNOS via the HMGB1-TLR4-Caveolin-1 pathway. On the other hand, increased oxLDLs lead to sustained activation of the scavenger receptor LOX-1 and, subsequently, to NFkB activation, which, in turn, increases iNOS, leading to EC oxidative stress. Finally, these events are associated with reduced protective autophagic response and accelerated apoptotic EC death, which activates atherosclerotic development. Taken together, this information sheds new light on the pathophysiological mechanisms of oxLDL-related impairment of EC functionality and opens new perspectives in atherothrombosis prevention.

scholarly journals Fortilin reduces apoptosis in macrophages and promotes atherosclerosis

2013 ◽  
Vol 305 (10) ◽  
pp. H1519-H1529 ◽  
Author(s):  
Decha Pinkaew ◽  
Rachel J. Le ◽  
Yanjie Chen ◽  
Mahmoud Eltorky ◽  
Ba-Bie Teng ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Oxidized Ldl ◽  
Ldl Receptor ◽  
Peritoneal Macrophages ◽  
Chow Diet ◽  
Mrna Editing ◽  
Atherosclerotic Lesions ◽  
Normal Chow ◽  
Induced Apoptosis ◽  
Editing Enzyme

Atherosclerosis, a deadly disease insufficiently addressed by cholesterol-lowering drugs, needs new therapeutic strategies. Fortilin, a 172-amino acid multifunctional polypeptide, binds p53 and blocks its transcriptional activation of Bax, thereby exerting potent antiapoptotic activity. Although fortilin-overexpressing mice reportedly exhibit hypertension and accelerated atherosclerosis, it remains unknown if fortilin, not hypertension, facilitates atherosclerosis. Our objective was to test the hypothesis that fortilin in and of itself facilitates atherosclerosis by protecting macrophages against apoptosis. We generated fortilin-deficient ( fortilin+/−) mice and wild-type counterparts ( fortilin+/+) on a LDL receptor ( Ldlr)−/− apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 ( Apobec1)−/− hypercholesterolemic genetic background, incubated them for 10 mo on a normal chow diet, and assessed the degree and extent of atherosclerosis. Despite similar blood pressure and lipid profiles, fortilin+/− mice exhibited significantly less atherosclerosis in their aortae than their fortilin +/+ littermate controls. Quantitative immunostaining and flow cytometry analyses showed that the atherosclerotic lesions of fortilin+/− mice contained fewer macrophages than those of fortilin+/+ mice. In addition, there were more apoptotic cells in the intima of fortilin+/− mice than in the intima of fortilin+/+ mice. Furthermore, peritoneal macrophages from fortilin+/− mice expressed more Bax and underwent increased apoptosis, both at the baseline level and in response to oxidized LDL. Finally, hypercholesterolemic sera from Ldlr−/− Apobec1−/− mice induced fortilin in peritoneal macrophages more robustly than sera from control mice. In conclusion, fortilin, induced in the proatherosclerotic microenvironment in macrophages, protects macrophages against Bax-induced apoptosis, allows them to propagate, and accelerates atherosclerosis. Anti-fortilin therapy thus may represent a promising next generation antiatherosclerotic therapeutic strategy.

scholarly journals Myriocin and d-PDMP ameliorate atherosclerosis in ApoE−/− mice via reducing lipid uptake and vascular inflammation

2020 ◽  
Vol 134 (5) ◽  
pp. 439-458 ◽  
Author(s):  
Zemou Yu ◽  
Qing Peng ◽  
Songyue Li ◽  
Hongjun Hao ◽  
Jianwen Deng ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Vascular Inflammation ◽  
Cell Formation ◽  
Ldl Receptor ◽  
Foam Cell Formation ◽  
Lipid Uptake ◽  
Atherosclerosis Progression

Abstract Sphingolipids have been implicated in the etiology of atherosclerosis. The commonly used sphingolipid inhibitors, myriocin (a ceramide inhibitor) and d-PDMP (d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, a glycosphingolipid inhibitor), have shown therapeutic potential but their efficacy and their underlying mechanisms remain unclear. Here, apolipoprotein E-deficient (apoE−/−) mice were fed a high-fat diet (HFD) and treated with a control, myriocin, d-PDMP, or atorvastatin for 12 weeks. We analyzed the effects of these drugs on the size and detailed composition of atherosclerotic plaques. Molecular biological approaches were used to explore how the inhibitors affect lipid metabolism and foam-cell formation. Treatment with myriocin or d-PDMP led to smaller and less vulnerable atherosclerotic lesions and was almost as effective as atorvastatin. Sphingolipid inhibitors down-regulated the expression of monocyte chemotactic protein 1 (MCP-1) and its receptor chemoattractant cytokine receptor 2 (CCR2), which play a key role in monocyte recruitment. They also decreased pro-inflammatory Ly-6chigh monocytes and influenced the uptake of modified LDL by down-regulating the expression of cluster of differentiation 36 (CD36) and lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1). The inhibitors exhibited the advantage of maintaining normal glucose homeostasis compared with atorvastatin. These findings reveal for the first time that the modulation of sphingolipid synthesis can effectively alleviate atherosclerosis progression by preventing lipid uptake and reducing inflammatory responses in the arterial walls.

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

2009 ◽  
Vol 296 (5) ◽  
pp. H1643-H1650 ◽  
Author(s):  
Heather H. Shih ◽  
Songwen Zhang ◽  
Wei Cao ◽  
Ashleigh Hahn ◽  
Juan Wang ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Ligand Binding ◽  
Oxidized Ldl ◽  
Vascular Inflammation ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Direct Interaction ◽  
Binding Studies ◽  
Binding Interface ◽  
Arginine Residues

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.

Exogenous l-Arginine and HDL Can Alter LDL and ox-LDL-Mediated Platelet Activation

2010 ◽  
Vol 17 (6) ◽  
pp. E79-E86 ◽  
Author(s):  
Azize Sener ◽  
Elif Enc ◽  
Derya Ozsavci ◽  
Birgul Vanizor-Kural ◽  
Gulderen Yanikkaya-Demirel ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Flow Cytometry ◽  
Platelet Activation ◽  
Oxidized Ldl ◽  
Ldl Receptor ◽  
Adenosine Diphosphate ◽  
Activated Platelets

The aim of this study is to investigate the effects of exogenous l-arginine and HDL on LDL and oxidized LDL (ox-LDL)-mediated platelet activation. Adenosine diphosphate (ADP)-activated platelets have been incubated with lipoproteins with or without l-arginine. P-selectin receptor numbers per platelet have been measured by flow cytometry. After incubation with only l-arginine (without lipoproteins), platelet nitric oxide (NO) levels and P-selectin receptor numbers significantly increased compared to the controls ( P < .05). After incubation with LDL or ox-LDL, receptor numbers of P-selectin significantly increased ( P < .001). However, P-selectin receptor numbers in platelets treated with l-arginine + LDL or l-arginine + ox-LDL decreased compared to the levels in platelets treated with only LDL or ox-LDL ( P < .01, P < .001, respectively). Addition of HDL to l-arginine + ox-LDL caused significant reduction in P-selectin receptor numbers as in the control values ( P < .001).We have concluded that l-arginine causes enhanced platelet NO levels and blocks the effects of LDL or ox-LDL on platelet P-selectin receptor numbers and HDL also strengthens this effect of l-arginine.

scholarly journals Exploring the Antihypertensive and Vascular-Protective Effects of Blueberries in Middle-Aged/Older Men: Study Protocol

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1745-1745
Author(s):  
Emily Woolf ◽  
Allegra Vazquez ◽  
Sarah Johnson
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Arterial Stiffness ◽  
Endothelial Function ◽  
Vascular System ◽  
Oxidized Ldl ◽  
Reactive Hyperemia ◽  
Protective Effects ◽  
Freeze Dried ◽  
Stage 1

Abstract Objectives Previous research has demonstrated the antihypertensive and vascular-protective effects of blueberries in postmenopausal women with elevated blood pressure (BP) or stage 1-hypertension (HTN). However, this has not been explored in men with elevated BP or HTN. The objective of the present study is to examine effects of blueberry (BB) on BP, endothelial function, and arterial stiffness in men with elevated BP or stage 1-HTN, and baseline endothelial dysfunction, as well as to investigate possible mechanisms involved with BB on vascular health. Methods In a randomized, double-blind, placebo-controlled, parallel-arm trial, men with elevated BP or stage 1-HTN (systolic BP of 120–139 mmHg, and a diastolic BP &lt; 90 mmHg), and endothelial dysfunction (reactive hyperemia index, RHI) &lt;1.67, but otherwise healthy, will be randomized to receive either 22 g/day of freeze-dried wild BB powder or 22 g/day of placebo powder for 12 weeks. Primary outcomes for this study are BP and RHI, which is a measure of vascular endothelial function assessed using peripheral arterial tonometry. Secondary outcomes include analysis of arterial stiffness, measured by pulse wave velocity (PWV), as well as blood biomarkers of cardiovascular and metabolic health that include blood lipids, hemoglobin A1c, oxidized LDL, nitric oxide, and adhesion molecules. Furthermore, endothelial cells will be biopsied to provide mechanistic insight on how BB consumption might affect the vascular system by utilizing quantitative immunofluorescence. Results We hypothesize that 22 g/day of BB consumption (∼1 cup) for 12 weeks will improve endothelial function, arterial stiffness, and BP in men with elevated BP and/or stage 1-HTN. We also hypothesize that these improvements will be mediated by reductions in vascular oxidative stress and inflammation, and increased nitric oxide bioavailability. Conclusions This study has potential to provide unique in vivo (functional) and ex vivo (molecular) support for the hypothesis that BB consumption may attenuate endothelial dysfunction, arterial stiffness, and high BP that occurs with aging. Funding Sources Wild Blueberry Association of North America.

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