scholarly journals Constitutive and stimulated macropinocytosis in macrophages: roles in immunity and in the pathogenesis of atherosclerosis

2018 ◽  
Vol 374 (1765) ◽  
pp. 20180147 ◽  
Author(s):  
Sasha A. Doodnauth ◽  
Sergio Grinstein ◽  
Michelle E. Maxson
Keyword(s):  
Foam Cell ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Immune Surveillance ◽  
Density Lipoprotein ◽  
Unique Type ◽  
Functional Roles ◽  
Fluid Uptake ◽  
Molecular Patterns

Macrophages respond to several stimuli by forming florid membrane ruffles that lead to fluid uptake by macropinocytosis. This type of induced macropinocytosis, executed by a variety of non-malignant and malignant cells, is initiated by transmembrane receptors and is involved in nutrient acquisition and mTOR signalling. However, macrophages also perform a unique type of constitutive ruffling and macropinocytosis that is dependent on the presence of extracellular calcium. Calcium-sensing receptors are responsible for this activity. This distinct form of macropinocytosis enables macrophages to continuously sample their microenvironment for antigenic molecules and for pathogen- and danger-associated molecular patterns, as part of their immune surveillance functions. Interestingly, even within the monocyte lineage, there are differences in macropinocytic ability that reflect the polarized functional roles of distinct macrophage subsets. This review discusses the shared and distinct features of both induced and constitutive macropinocytosis displayed by the macrophage lineage and their roles in physiology, immunity and pathophysiology. In particular, we analyse the role of macropinocytosis in the uptake of modified low-density lipoprotein (LDL) and its contribution to foam cell and atherosclerotic plaque formation. We propose a combined role of scavenger receptors and constitutive macropinocytosis in oxidized LDL uptake, a process we have termed ‘receptor-assisted macropinocytosis'. This article is part of the Theo Murphy meeting issue ‘Macropinocytosis’.

Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christina Grothusen ◽  
Harald Schuett ◽  
Stefan Lumpe ◽  
Andre Bleich ◽  
Silke Glage ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

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

scholarly journals Role of Lectin-Like Oxidized Low Density Lipoprotein-1 in Fetoplacental Vascular Dysfunction in Preeclampsia

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Felipe A. Zuniga ◽  
Valeska Ormazabal ◽  
Nicolas Gutierrez ◽  
Valeria Aguilera ◽  
Claudia Radojkovic ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Dysfunction ◽  
Pathological Condition ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Fetal Loss ◽  
Density Lipoprotein ◽  
Placental Tissue

The bioavailability of nitric oxide (NO) represents a key marker in vascular health. A decrease in NO induces a pathological condition denominated endothelial dysfunction, syndrome observed in different pathologies, such as obesity, diabetes, kidney disease, cardiovascular disease, and preeclampsia (PE). PE is one of the major risks for maternal death and fetal loss. Recent studies suggest that the placenta of pregnant women with PE express high levels of lectin-like oxidized LDL receptor-1 (LOX-1), which induces endothelial dysfunction by increasing reactive oxygen species (ROS) and decreasing intracellular NO. Besides LOX-1 activation induces changes in migration and apoptosis of syncytiotrophoblast cells. However, the role of this receptor in placental tissue is still unknown. In this review we will describes the physiological roles of LOX-1 in normal placenta development and the potential involvement of this receptor in the pathophysiology of PE.

Abstract 15833: LRP1 is a Novel Receptor of Bmper and Required for Pathological Angiogenesis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Xi Li ◽  
Xinchun Pi
Keyword(s):  
Endothelial Cells ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Bmp Signaling ◽  
Functional Roles ◽  
Oxygen Induced Retinopathy ◽  
Morphogenetic Protein ◽  
Density Lipoprotein Receptor

Low density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional member of the LDL receptor family, impacting a variety of biological processes such as lipid metabolism, endocytosis and signal transduction. However, the role of LRP1 in endothelium was almost unknown. Until recently we discovered that LRP1 is a novel regulator of bone morphogenetic protein (Bmp) signaling through its association with the extracellular modulator-Bmper (Bmp-binding endothelial cell precursor-derived regulator) and regulates zebrafish vascular development. Here we studied the functional roles of LRP1 in mammalian system by performing cell culture studies with endothelial cells (ECs) and analyzing angiogenic defects in oxygen-induced retinopathy model with LRP1flox/flox;Tie2-Cre+/- mice (EC-LRP1 KO). In MECs, we observed that the activation of Src, ERK and tyrosine phosphorylation of multiple proteins were induced by Bmper and this activation was LRP1-dependent since LRP1 knockdown inhibited their activation. However, this Bmper-induced activation was not blocked by Bmp4 neutralized antibody, which suggests that LRP1 is required for Bmp4-independent signaling for Bmper. These data also indicate that Bmper and LRP1 is a novel ligand receptor pair. Moreover, we observed that LRP1 protein was induced in response to 1% hypoxia in both mouse ECs (MECs) and human retinal microvascular endothelial cells, suggesting that LRP1 is required for hypoxia induced endothelial function. In hypoxia condition, EC-LRP1 KO mice resulted in accelerated angiogenesis in retinal endothelial cells, similar to the pattern of Bmper deleted mice. Therefore, we identify that the Bmper/LRP1 signaling is a novel signaling pathway in endothelial cells and their activity regulates angiogenic responses during oxygen-induced retinopathy. This study provides mechanistic insights for angiogenesis-related pathophysiologic conditions.

Low density lipoprotein increases amyloid precursor protein processing to amyloidogenic pathway in differentiated SH-SY5Y cells

Biologia ◽  
2017 ◽  
Vol 72 (2) ◽  
Author(s):  
Panit Yamchuen ◽  
Rattima Jeenapongsa ◽  
Sutisa Nudmamud-Thanoi ◽  
Nanteetip Limpeanchob
Keyword(s):  
Amyloid Precursor Protein ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Neuroblastoma Cells ◽  
Density Lipoprotein ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Low Density ◽  
App Processing

AbstractHypercholesterolemia has been considered as a risk factor for Alzheimer’s disease (AD). In addition to low density lipoprotein (LDL), oxidized LDL plays some roles in AD pathology. Neurodegenerative effect of oxidized LDL was supported by the increased oxidative stress in neurons. To further investigate the role of oxidized LDL, the present study aimed to test its effect on amyloid precursor protein (APP) processing. The release of soluble APP (sAPP) was evaluated in differentiated SH-SY5Y neuroblastoma cells exposed to native (non-oxidized) or oxidized human LDL including mildly and fully oxidized LDL (mox- and fox-LDL). Non-amyloidogenic and amyloidogenic pathways were investigated using specific antibody against sAPP

Rubus coreanusInhibits Oxidized-LDL Uptake by Macrophages Through Regulation of JNK Activation

2012 ◽  
Vol 40 (05) ◽  
pp. 967-978 ◽  
Author(s):  
Bidur Bhandary ◽  
Geum-Hwa Lee ◽  
Byung-Ok So ◽  
Sun-Young Kim ◽  
Min-Gul Kim ◽  
...  
Keyword(s):  
Foam Cell ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Blood Stasis ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Rubus Coreanus ◽  
Dose Dependent

Oxidized low-density lipoprotein (oxLDL) contributes to atherosclerosis in part by being taken up into macrophages via scavenger receptors and leading to foam cell formation. Herbal compounds that have been used to treat blood stasis (a counterpart of atherosclerosis) for centuries include extracts of medicinal plants in the Rosaceae and Leguminosae families. In this study, we investigated the effect of the unripe Rubus coreanus (Korean black raspberry) fruit extract on oxLDL uptake by murine macrophage cells. In the presence of Rubus coreanus extract (RCE), Dil-labeled oxLDL uptake was inhibited in a dose-dependent manner. SP600125, a specific JNK inhibitor, inhibited the uptake of Dil-oxLDL into macrophages. RCE also inhibited JNK phosphorylation in a time- and dose-dependent manner in macrophages treated with oxLDL. These results indicate that among the mitogen-activated protein kinases, JNK phosphorylation is inhibited by RCE, which is likely the mechanism underlying the RCE-induced inhibition of oxLDL uptake by macrophages.

scholarly journals Recognition of Oxidized Lipids by Macrophages and Its Role in Atherosclerosis Development

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 915
Author(s):  
Nataliya V. Mushenkova ◽  
Evgeny E. Bezsonov ◽  
Varvara A. Orekhova ◽  
Tatyana V. Popkova ◽  
Antonina V. Starodubova ◽  
...  
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Formation Mechanisms ◽  
Therapeutic Approaches ◽  
Macrophage Response ◽  
New Therapeutic Approaches ◽  
Metabolic Imbalance ◽  
Atherosclerosis Development

Atherosclerosis is a multifactorial chronic disease that has a prominent inflammatory component. Currently, atherosclerosis is regarded as an active autoimmune process that involves both innate and adaptive immune pathways. One of the drivers of this process is the presence of modified low-density lipoprotein (LDL). For instance, lipoprotein oxidation leads to the formation of oxidation-specific epitopes (OSE) that can be recognized by the immune cells. Macrophage response to OSEs is recognized as a key trigger for initiation and a stimulator of progression of the inflammatory process in the arteries. At the same time, the role of oxidized LDL components is not limited to pro-inflammatory stimulation, but includes immunoregulatory effects that can have protective functions. It is, therefore, important to better understand the complexity of oxidized LDL effects in atherosclerosis in order to develop new therapeutic approaches to correct the inflammatory and metabolic imbalance associated with this disorder. In this review, we discuss the process of oxidized LDL formation, mechanisms of OSE recognition by macrophages and the role of these processes in atherosclerosis.

scholarly journals Polar phospholipids from bovine endogenously oxidized low density lipoprotein interfere with follicular thecal function

2005 ◽  
Vol 35 (3) ◽  
pp. 531-545 ◽  
Author(s):  
B Löhrke ◽  
T Viergutz ◽  
B Krüger
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Ldl Oxidation ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein ◽  
Steroidogenic Enzymes ◽  
Cox 2

The role of endogenously oxidized low density lipoprotein (oxLDL) in follicular steroidogenic regulation is unknown. Information may be important in order to elucidate ovulatory dysregulation in disordered lipid metabolism. To obtain specific data, we studied the effect of polar phospholipids (PL) isolated from oxLDL with different endogenous levels of lipohydroperoxides (LHP) on the thecal expression of mRNA encoding steroidogenic enzymes and cyclooxygenase 2 (COX-2), and on the thecal production of superoxide and progesterone. Large (preovulatory) bovine follicles were used and analyses of thecal fragments from single follicles were performed by radioimmunoassays, chemiluminescence assays and quantitative RT-PCR. Basal concentration of mRNA for several lipoprotein receptors exceeded by about 10-times the basal level of mRNA encoding steroidogenic enzymes, suggesting that preovulatory theca receptors may favour uptake of oxLDL. PL (5–11 pmol phosphorus/ml) decreased (up to 0.5-times the control) progesterone synthesis, production of superoxide and levels of P450 cholesterol side chain cleavage (P450 scc), 3β-hydroxysteroid dehydrogenase and COX-2 mRNA. Abundance of COX-2 transcripts in thecal tissue incubated with forskolin depended on the progesterone/17β-oestradiol ratio of the follicle fluid, i.e. the previous microenvironment in vivo. PL effects were mimicked by the platelet-activating factor (PAF). WEB 2086, a PAF receptor blocker, did not always abolish these responses, suggesting that the effects were not mediated solely by this receptor. PAF interfered dose-dependently with LH-induced responses, indicating interference with LH signalling. PL from mildly oxidized LDL (0.5 nmol/ml LHP) tended to exert greater effects than PL from oxLDL containing 1.5 nmol/ml LHP. In consideration of the known physiologic role of progesterone, COX-2 and possibly superoxide, these results provide evidence for a potential of PL from oxLDL to induce ovulatory dysregulation and suggest that the extent of the LDL oxidation seems to be important for interfering with thecal responses to the preovulatory LH surge.

scholarly journals Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

2020 ◽  
Author(s):  
Zhongli Chen ◽  
Qiqi Xue ◽  
Lijuan Cao ◽  
Yanpin Wang ◽  
Yuanyuan Chen ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Src Kinase ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cell Phenotype ◽  
Ros Accumulation ◽  
Sirt3 Expression

Abstract Background: Oxidized low-density lipoprotein (oxLDL) induced a foam-cell like phenotype of the vascular smooth muscle cells (VSMCs), leading to the inflammatory responses incorporating Toll-like receptors (Tlrs)-mediated cellular alterations. We previously found that Tlr4 participated in inflammation response in VSMCs under oxLDL stimulation. However, the role of Tlr4 in foam-cell formation and underlying molecular pathways has not been comprehensively elucidated. This study aimed to investigate the role of Tlr4-mediated mechanisms in oxLDL induced foam-cell formation within VSMCs. Methods: After incubated with different dose of oxLDL, the lipid, reactive oxygen species (ROS) accumulation and foam-cell phenotype of the VSMCs were detected. The alteration of Tlr family, ROS and lipid accumulation regulators including the Src kinase, Nox2, Nox4, Mnsod and sirtuins were measured. Then the Tlr4 was knock down and underlying cellular change and altered molecules were detected. Results: We showed that oxLDL induced foam-cell like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. OxLDL induced the strongest upregulation of Tlr4 in the Tlrs family and initiated change of Src activation, Nox2, Mnsod, sirt1 and sirt3 expression. The effect of oxLDL was abolished by Tlr4 knockdown. Furthermore, knocking down of Tlr4 reduced Src activation and led to restored Sirt1/Sirt3 expression. Moreover, inhibiting or knocking down the Src kinase diminished lipid accumulation in VSMCs under oxLDL treatment. And overexpression of Sirt1/3 relieved the oxLDL induced ROS accumulation and foam-cell phenotype in VSMCs.Conclusions: These results demonstrated that Tlr4 is a critical regulator in oxLDL induced foam cell formation of VSMCs via mediating Src kinase as well as Sirt1 and Sirt3. Beyond the role of Tlr4 in inflammation response of VSMCs, we provide an integrated mechanism about TLR4 in VSMCs phenotype transition under oxLDL stimulation.

scholarly journals Role of Lipid Accumulation and Inflammation in Atherosclerosis: Focus on Molecular and Cellular Mechanisms

2021 ◽  
Vol 8 ◽  
Author(s):  
Khojasteh Malekmohammad ◽  
Evgeny E. Bezsonov ◽  
Mahmoud Rafieian-Kopaei
Keyword(s):  
Lipid Accumulation ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Endothelial Damage ◽  
Lipid Homeostasis ◽  
Foam Cell Formation ◽  
Low Density ◽  
Cellular Mechanisms

Atherosclerosis is a chronic lipid-driven and maladaptive inflammatory disease of arterial intima. It is characterized by the dysfunction of lipid homeostasis and signaling pathways that control the inflammation. This article reviews the role of inflammation and lipid accumulation, especially low-density lipoprotein (LDL), in the pathogenesis of atherosclerosis, with more emphasis on cellular mechanisms. Furthermore, this review will briefly highlight the role of medicinal plants, long non-coding RNA (lncRNA), and microRNAs in the pathophysiology, treatment, and prevention of atherosclerosis. Lipid homeostasis at various levels, including receptor-mediated uptake, synthesis, storage, metabolism, efflux, and its impairments are important for the development of atherosclerosis. The major source of cholesterol and lipid accumulation in the arterial wall is proatherogenic modified low-density lipoprotein (mLDL). Modified lipoproteins, such as oxidized low-density lipoprotein (ox-LDL) and LDL binding with proteoglycans of the extracellular matrix in the intima of blood vessels, cause aggregation of lipoprotein particles, endothelial damage, leukocyte recruitment, foam cell formation, and inflammation. Inflammation is the key contributor to atherosclerosis and participates in all phases of atherosclerosis. Also, several studies have shown that microRNAs and lncRNAs have appeared as key regulators of several physiological and pathophysiological processes in atherosclerosis, including regulation of HDL biogenesis, cholesterol efflux, lipid metabolism, regulating of smooth muscle proliferation, and controlling of inflammation. Thus, both lipid homeostasis and the inflammatory immune response are closely linked, and their cellular and molecular pathways interact with each other.

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