scholarly journals Proteolytic Regulation of the Lectin-Like Oxidized Lipoprotein Receptor LOX-1

2021 ◽  
Vol 7 ◽  
Author(s):  
Torben Mentrup ◽  
Florencia Cabrera-Cabrera ◽  
Bernd Schröder
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Soluble Form ◽  
Foam Cell Formation ◽  
Protective Mechanism ◽  
Vascular Cells ◽  
Diagnostic Potential ◽  
Proteolytic Cleavages

The lectin-like oxidized-LDL (oxLDL) receptor LOX-1, which is broadly expressed in vascular cells, represents a key mediator of endothelial activation and dysfunction in atherosclerotic plaque development. Being a member of the C-type lectin receptor family, LOX-1 can bind different ligands, with oxLDL being the best characterized. LOX-1 mediates oxLDL uptake into vascular cells and by this means can promote foam cell formation. In addition, LOX-1 triggers multiple signaling pathways, which ultimately induce a pro-atherogenic and pro-fibrotic transcriptional program. However, the molecular mechanisms underlying this signal transduction remain incompletely understood. In this regard, proteolysis has recently emerged as a regulatory mechanism of LOX-1 function. Different proteolytic cleavages within the LOX-1 protein can initiate its turnover and control the cellular levels of this receptor. Thereby, cleavage products with individual biological functions and/or medical significance are produced. Ectodomain shedding leads to the release of a soluble form of the receptor (sLOX1) which has been suggested to have diagnostic potential as a biomarker. Removal of the ectodomain leaves behind a membrane-bound N-terminal fragment (NTF), which despite being devoid of the ligand-binding domain is actively involved in signal transduction. Degradation of this LOX-1 NTF, which represents an athero-protective mechanism, critically depends on the aspartyl intramembrane proteases Signal peptide peptidase-like 2a and b (SPPL2a/b). Here, we present an overview of the biology of LOX-1 focusing on how proteolytic cleavages directly modulate the function of this receptor and, what kind of pathophysiological implications this has in cardiovascular disease.

Abstract 17333: Myeloid-Specific Deletion of Epsins 1 and 2 Reduces Atherosclerosis by Preventing LRP-1 Downregulation

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Hong Chen ◽  
Megan Brophy
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Cell ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
Macrophage Phenotype ◽  
Double Knockout ◽  
Cell Content ◽  
Inflammatory Macrophage

Introduction: Atherosclerosis is in part caused by immune and inflammatory cell infiltration into the vascular wall, leading to enhanced inflammation and lipid accumulation in the aortic endothelium. Understanding the molecular mechanisms underlying this disease is critical for the development of new therapies. Our recent studies demonstrate that epsins, a family of ubiquitin-binding endocytic adaptors, are critical regulators of atherogenicity. Given the fundamental contribution lesion macrophages make to fuel atherosclerosis, whether and how myeloid specific epsins promote atherogenesis is an open and significant question. Hypothesis: We hypothesize that myeloid specific epsins regulate lesion macrophage function during atherosclerosis. Methods and Results: We engineered myeloid cell-specific epsins double knockout mice (LysM-DKO)on an ApoE -/- background. On Western diet, these mice exhibited marked decrease in atherosclerotic lesion formation, diminished immune and inflammatory cell content in aortas, and reduced necrotic core content but increased smooth muscle cell content in aortic root sections.Epsins deficiency hindered foam cell formation and suppressed the pro-inflammatory macrophage phenotype but increased efferocytosis and the anti-inflammatory macrophage phenotype in primary macrophages.Mechanistically, we show that epsins loss specifically increased total and surface levels of LRP-1, an efferocytosis receptor with anti-atherosclerotic properties. We further show thatepsin and LRP-1 interact via epsin’s Ubiquitin Interacting Motif (UIM) domain. Oxidized LDL treatment increased LRP-1 ubiquitination and subsequent binding to epsin while mutation of cytoplasmic lysine residues attenuated LRP-1 ubiquitination, suggesting that epsins promote the ubiquitin-dependent internalization and downregulation of LRP-1. Crossing ApoE -/- /LysM-DKO mice onto a LRP-1 heterozygous background restored, in part, atherosclerosis, suggesting that epsin-mediated LRP-1 downregulation in macrophages plays a pivotal role in propelling atherogenesis. Conclusions: Myeloid epsins promote atherogenesis by facilitating pro-inflammatory macrophage recruitment and inhibiting efferocytosis in part by downregulating LRP-1, implicating that targeting epsins in macrophages may serve as a novel therapeutic strategy to treat atherosclerosis. Key words: epsin, macrophage, atherosclerosis, LRP-1, inflammation, efferocytosis

Abstract 94: Deficiency of Epsins in Macrophages Ameliorates Atherosclerosis by Attenuating Inflammation

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Megan L Brophy ◽  
Yunzhou Dong ◽  
Hao Wu ◽  
Kai Song ◽  
Ashiqur Rahman ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Cell ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Macrophage Phenotype ◽  
M1 Macrophage ◽  
Anti Inflammatory ◽  
Inflammatory Macrophage

Background: Atherosclerosis is caused by the immune and inflammatory cell infiltration of the vascular wall, leading to enhanced inflammation and lipid accumulation. Understanding the molecular mechanisms underlying this disease is critical for the development of new therapies. Our recently studies demonstrate that endothelial epsins, a family of ubiquitin-binding endocytic adaptors are critical regulators of atherosclerosis. However, whether epsins in macrophages play a role in regulating vascular inflammation is unknown. We hypothesize that epsins in macrophages promote inflammation to facilitate atherogenesis. Methods and Results: We engineered myeloid cell-specific epsins double knockout mice (MΦ-DKO) on an ApoE-/- background fed western diet. Strikingly, these mice exhibited reduced atherosclerotic lesion formation, diminished immune and inflammatory cell recruitment to aortas and reduced cleaved caspase 3 staining but increased α-SMA staining within aortic root sections. Epsin deficiency hindered foam cell formation, suppressed the pro-inflammatory M1 macrophage phenotype but increased the anti-inflammatory macrophage phenotype, and enhanced efferocytosis in primary macrophages. Mechanistically, we show that epsin loss specifically increases total and surface levels of LRP-1, a protein with anti-inflammatory properties without altering levels of LDL scavenger receptors. We further show that epsin and LRP-1 interact via epsin’s UIM domain. Oxidized LDL treatment increased LRP-1 ubiquitination and subsequent binding to epsin while mutation of cytoplasmic lysine residues attenuated LRP-1 ubiquitination, suggesting that epsin promotes the ubiquitin-dependent internalization and degradation of LRP-1. Importantly, MΦ-DKO/ApoE null mice on LRP-1 heterozygous background restored atherosclerosis, suggesting that epsin-mediated LRP-1 downregulation in macrophages plays a pivotal role in propelling atherogenesis. Conclusions: Macrophage epsins promote atherogenesis, in part, by facilitating pro-inflammatory macrophage recruitment and potentiating foam cell formation by downregulating LRP-1, implicating that targeting epsin in macrophages may serve as a novel therapeutic strategy to treat atheroma.

The Anti-Atherogenic Properties of Sesamin are Mediated via Improved Macrophage Cholesterol Efflux Through PPARγ1-LXRα and MAPK Signaling

2014 ◽  
Vol 84 (1-2) ◽  
pp. 79-91 ◽  
Author(s):  
Amin F. Majdalawieh ◽  
Hyo-Sung Ro
Keyword(s):  
Cholesterol Efflux ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Mapk Signaling ◽  
Luciferase Reporter ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Macrophage Cholesterol Efflux

Background: Foam cell formation resulting from disrupted macrophage cholesterol efflux, which is triggered by PPARγ1 and LXRα, is a hallmark of atherosclerosis. Sesamin and sesame oil exert anti-atherogenic effects in vivo. However, the exact molecular mechanisms underlying such effects are not fully understood. Aim: This study examines the potential effects of sesamin (0, 25, 50, 75, 100 μM) on PPARγ1 and LXRα expression and transcriptional activity as well as macrophage cholesterol efflux. Methods: PPARγ1 and LXRα expression and transcriptional activity are assessed by luciferase reporter assays. Macrophage cholesterol efflux is evaluated by ApoAI-specific cholesterol efflux assays. Results: The 50 μM, 75 μM, and 100 μM concentrations of sesamin up-regulated the expression of PPARγ1 (p< 0.001, p < 0.001, p < 0.001, respectively) and LXRα (p = 0.002, p < 0.001, p < 0.001, respectively) in a concentration-dependent manner. Moreover, 75 μM and 100 μM concentrations of sesamin led to 5.2-fold (p < 0.001) and 6.0-fold (p<0.001) increases in PPAR transcriptional activity and 3.9-fold (p< 0.001) and 4.2-fold (p < 0.001) increases in LXR transcriptional activity, respectively, in a concentration- and time-dependent manner via MAPK signaling. Consistently, 50 μM, 75 μM, and 100 μM concentrations of sesamin improved macrophage cholesterol efflux by 2.7-fold (p < 0.001), 4.2-fold (p < 0.001), and 4.2-fold (p < 0.001), respectively, via MAPK signaling. Conclusion: Our findings shed light on the molecular mechanism(s) underlying sesamin’s anti-atherogenic effects, which seem to be due, at least in part, to its ability to up-regulate PPARγ1 and LXRα expression and transcriptional activity, improving macrophage cholesterol efflux. We anticipate that sesamin may be used as a therapeutic agent for treating atherosclerosis.

scholarly journals Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia

2021 ◽  
Vol 22 (2) ◽  
pp. 660
Author(s):  
María Aguilar-Ballester ◽  
Gema Hurtado-Genovés ◽  
Alida Taberner-Cortés ◽  
Andrea Herrero-Cervera ◽  
Sergio Martínez-Hervás ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Leukocyte Adhesion ◽  
Experimental Studies ◽  
Lipid Lowering ◽  
Foam Cell Formation ◽  
Relevant Parameter

Cardiovascular disease (CVD) is the leading cause of death worldwide and is the clinical manifestation of the atherosclerosis. Elevated LDL-cholesterol levels are the first line of therapy but the increasing prevalence in type 2 diabetes mellitus (T2DM) has positioned the cardiometabolic risk as the most relevant parameter for treatment. Therefore, the control of this risk, characterized by dyslipidemia, hypertension, obesity, and insulin resistance, has become a major goal in many experimental and clinical studies in the context of CVD. In the present review, we summarized experimental studies and clinical trials of recent anti-diabetic and lipid-lowering therapies targeted to reduce CVD. Specifically, incretin-based therapies, sodium-glucose co-transporter 2 inhibitors, and proprotein convertase subtilisin kexin 9 inactivating therapies are described. Moreover, the novel molecular mechanisms explaining the CVD protection of the drugs reviewed here indicate major effects on vascular cells, inflammatory cells, and cardiomyocytes, beyond their expected anti-diabetic and lipid-lowering control. The revealed key mechanism is a prevention of acute cardiovascular events by restraining atherosclerosis at early stages, with decreased leukocyte adhesion, recruitment, and foam cell formation, and increased plaque stability and diminished necrotic core in advanced plaques. These emergent cardiometabolic therapies have a promising future to reduce CVD burden.

scholarly journals Anti-Atherosclerotic Activity of (3R)-5-Hydroxymellein from an Endophytic Fungus Neofusicoccum parvum JS-0968 Derived from Vitex rotundifolia through the Inhibition of Lipoproteins Oxidation and Foam Cell Formation

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 715
Author(s):  
Jae-Yong Kim ◽  
Soonok Kim ◽  
Sang Hee Shim
Keyword(s):  
Conformational Changes ◽  
Endophytic Fungus ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Ldl Oxidation ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Neofusicoccum Parvum

An endophytic fungus, Neofusicoccum parvum JS-0968, was isolated from a plant, Vitex rotundifolia. The chemical investigation of its cultures led to the isolation of a secondary metabolite, (3R)-5-hydroxymellein. It has been reported to have antifungal, antibacterial, and antioxidant activity, but there have been no previous reports on the effects of (3R)-5-hydroxymellein on atherosclerosis. The oxidation of lipoproteins and foam cell formation have been known to be significant in the development of atherosclerosis. Therefore, we investigated the inhibitory effects of (3R)-5-hydroxymellein on atherosclerosis through low-density lipoprotein (LDL) and high-density lipoprotein (HDL) oxidation and macrophage foam cell formation. LDL and HDL oxidation were determined by measuring the production of conjugated dienes and malondialdehyde, the amount of hyperchromicity and carbonyl content, conformational changes, and anti-LDL oxidation. In addition, the inhibition of foam cell formation was measured by Oil red O staining. As a result, (3R)-5-hydroxymellein suppressed the oxidation of LDL and HDL through the inhibition of lipid peroxidation, the decrease of negative charges, the reduction of hyperchromicity and carbonyl contents, and the prevention of apolipoprotein A-I (ApoA-I) aggregation and apoB-100 fragmentation. Furthermore, (3R)-5-hydroxymellein significantly reduced foam cell formation induced by oxidized LDL (oxLDL). Taken together, our data show that (3R)-5-hydroxymellein could be a potential preventive agent for atherosclerosis via obvious anti-LDL and HDL oxidation and the inhibition of foam cell formation.

scholarly journals The Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 and Cardiovascular Disease

1970 ◽  
Vol 3 (2) ◽  
pp. 169-177
Author(s):  
MSA Sheikh ◽  
T Yang ◽  
U Salma ◽  
M Ali
Keyword(s):  
Signal Transduction ◽  
Endothelial Dysfunction ◽  
Morphological Changes ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Soluble Form ◽  
Low Density ◽  
Coronary Syndrome

Lectin-like oxidized LDL receptor-1 (LOX-1), a lectin-like 50-kD receptor for oxidized low-density lipoproteins (ox-LDL), is present primarily on endothelial cells. Oxidatively modified low-density lipoprotein (oxLDL) is implicated in the pathogenesis of atherosclerosis. Endothelial dysfunction is the initial change in the vascular wall that induces morphological changes for atheroma-formation. LOX-1 was identified as the receptor for oxLDL that was thought to be a major cause of endothelial dysfunction. LOX-1 has been demonstrated to contribute not only to endothelial dysfunction, but also to atherosclerotic-plaque formation, hypertension, myocardial infarction and intimal thickening after balloon injury. Studies with transgenic and knockout mouse models have elucidated in part the role of LOX-1 in the pathogenesis of atherosclerosis and cardiac remodeling. Recently, a circulating soluble form of LOX-1(sLOx-1), corresponding solely to its extracellular domain, has been identified in human serum. Circulating levels of sLOX-1 are increased in inflammatory and atherosclerotic conditions and are associated with acute coronary syndrome, with the severity of coronary artery disease, and with serum biomarkers for oxidative stress and inflammation, suggesting that they could be useful marker for vascular injury. Identification and regulation of this receptor and understanding of signal transduction pathways might open new gateways from diagnosis to therapeutics for cardiovascular diseases. Keywords: Atherosclerosis; Endothelial dysfunction; LOX-1; ox-LDL; Signal transduction. DOI: http://dx.doi.org/10.3329/cardio.v3i2.9187 Cardiovasc. J. 2011; 3(2): 169-177

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