Mechanisms of Dyslipoproteinemias in Systemic Lupus Erythematosus

Autoimmunity and inflammation are associated with marked changes in lipid and lipoprotein metabolism in SLE. Autoantibodies and cytokines are able to modulate lipoprotein lipase (LPL) activity, a key enzyme in lipid metabolism, with a consequent “lupus pattern” of dyslipoproteinemia characterized by elevated levels of very low-density lipoprotein cholesterol (VLDL) and triglycerides (TG) and lower high-density lipoprotein cholesterol (HDL) levels. This pattern favors an enhanced LDL oxidation with a subsequent deleterious foam cell formation. Autoantibodies and immunocomplexes may aggravate this oxidative injury by inducing accumulation and deposition of oxLDL in endothelial cells. Drugs and associated diseases usually magnify the close interaction of these factors and further promote the proatherogenic environment of this disease.

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Low-Density Lipoprotein Modified by Myeloperoxidase in Inflammatory Pathways and Clinical Studies

Mediators of Inflammation ◽

10.1155/2013/971579 ◽

2013 ◽

Vol 2013 ◽

pp. 1-18 ◽

Cited By ~ 42

Author(s):

Cédric Delporte ◽

Pierre Van Antwerpen ◽

Luc Vanhamme ◽

Thierry Roumeguère ◽

Karim Zouaoui Boudjeltia

Keyword(s):

Endothelial Cells ◽

Foam Cell ◽

Thrombus Formation ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Ldl Oxidation ◽

Foam Cell Formation ◽

Low Density ◽

Oxidized Lipoproteins

Oxidation of low-density lipoprotein (LDL) has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO) is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNFαand IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis.

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Interactions of Nitric Oxide and Peroxynitrite with Low-Density Lipoprotein

Biological Chemistry ◽

10.1515/bc.2002.055 ◽

2002 ◽

Vol 383 (3-4) ◽

pp. 547-552 ◽

Cited By ~ 43

Author(s):

H. Rubbo ◽

A. Trostchansky ◽

H. Botti ◽

C. Batthyány

Keyword(s):

Nitric Oxide ◽

Foam Cell ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Vascular Wall ◽

Ldl Oxidation ◽

Foam Cell Formation ◽

No Production ◽

Hydrophobic Core

Abstract Nitric oxide (NO) is a free radical species that diffuses and concentrates in the hydrophobic core of lowdensity lipoprotein (LDL) to serve as a potent inhibitor of lipid oxidation processes. Peroxynitrite (PN), the product of the diffusionlimited reaction between NO and superoxide (O2), represents a relevant mediator of oxidative modifications in LDL. The focus of this review is the analysis of interactions between NO and PN and its secondary reactions with oxygen radicals on LDL oxidation, which are relevant in the development of the early steps as well as progression of atherosclerosis. We propose that the balance between rates of PN and NO production, which greatly depends on oxidative stress processes within the vascular wall, will critically determine the final extent of oxidative LDL modifications leading or not to scavenger receptormediated LDL uptake and foam cell formation.

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ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/10742484211023639 ◽

2021 ◽

pp. 107424842110236

Author(s):

Dun Niu ◽

Lanfang Li ◽

Zhizhong Xie

Keyword(s):

Therapeutic Target ◽

Chloride Channels ◽

Foam Cell ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Molecular Structures ◽

Foam Cell Formation ◽

Endothelium Dysfunction ◽

Atherosclerotic Process

Chloride channel 3 (ClC-3), a Cl−/H+ antiporter, has been well established as a member of volume-regulated chloride channels (VRCCs). ClC-3 may be a crucial mediator for activating inflammation-associated signaling pathways by regulating protein phosphorylation. A growing number of studies have indicated that ClC-3 overexpression plays a crucial role in mediating increased plasma low-density lipoprotein levels, vascular endothelium dysfunction, pro-inflammatory activation of macrophages, hyper-proliferation and hyper-migration of vascular smooth muscle cells (VSMCs), as well as oxidative stress and foam cell formation, which are the main factors responsible for atherosclerotic plaque formation in the arterial wall. In the present review, we summarize the molecular structures and classical functions of ClC-3. We further discuss its emerging role in the atherosclerotic process. In conclusion, we explore the potential role of ClC-3 as a therapeutic target for atherosclerosis.

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Protective Effect of Lusianthridin on Hemin-Induced Low-Density Lipoprotein Oxidation

Pharmaceuticals ◽

10.3390/ph14060567 ◽

2021 ◽

Vol 14 (6) ◽

pp. 567

Author(s):

Su Wutyi Thant ◽

Noppawan Phumala Morales ◽

Visarut Buranasudja ◽

Boonchoo Sritularak ◽

Rataya Luechapudiporn

Keyword(s):

Foam Cell ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cell Formation ◽

Raw 264.7 ◽

Low Density ◽

Lipoprotein Oxidation ◽

Raw 264.7 Macrophage Cells ◽

Low Density Lipoprotein Oxidation

Oxidation of low-density lipoprotein (LDL) plays a crucial role in the pathogenesis of atherosclerosis. Hemin (iron (III)-protoporphyrin IX) is a degradation product of hemoglobin that can be found in thalassemia patients. Hemin is a strong oxidant that can cause LDL oxidation and contributes to atherosclerosis in thalassemia patients. Lusianthridin from Dendrobium venustrum is a phenolic compound that possesses antioxidant activity. Hence, lusianthridin could be a promising compound to be used against hemin-induced oxidative stress. The major goal of this study is to evaluate the protective effect of lusianthridin on hemin-induced low-density lipoprotein oxidation (he-oxLDL). Here, various concentrations of lusianthridin (0.25, 0.5, 1, and 2 µM) were preincubated with LDL for 30 min, then 5 µM of hemin was added to initiate the oxidation, and oxidative parameters were measured at various times of incubation (0, 1, 3, 6, 12, 24 h). Lipid peroxidation of LDL was measured by thiobarbituric reactive substance (TBARs) assay and relative electrophoretic mobility (REM). The lipid composition of LDL was analyzed by using reverse-phase HPLC. Foam cell formation with he-oxLDL in RAW 264.7 macrophage cells was detected by Oil Red O staining. The results indicated that lusianthridin could inhibit TBARs formation, decrease REM, decrease oxidized lipid products, as well as preserve the level of cholesteryl arachidonate and cholesteryl linoleate. Moreover, He-oxLDL incubated with lusianthridin for 24 h can reduce the foam cell formation in RAW 264.7 macrophage cells. Taken together, lusianthridin could be a potential agent to be used to prevent atherosclerosis in thalassemia patients.

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Phagocytosis of lipase-aggregated low density lipoprotein promotes macrophage foam cell formation. Sequential morphological and biochemical events.

Arteriosclerosis and Thrombosis A Journal of Vascular Biology ◽

10.1161/01.atv.11.6.1643 ◽

1991 ◽

Vol 11 (6) ◽

pp. 1643-1651 ◽

Cited By ~ 37

Author(s):

J W Heinecke ◽

A G Suits ◽

M Aviram ◽

A Chait

Keyword(s):

Foam Cell ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cell Formation ◽

Low Density ◽

Macrophage Foam Cell

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

Circulation ◽

10.1161/circ.118.suppl_18.s_467-c ◽

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.

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Epac1 regulates cellular SUMOylation by promoting the formation of SUMO-activating nuclear condensates

10.1101/2022.01.12.476066 ◽

2022 ◽

Author(s):

Wenli Yang ◽

William G Robichaux ◽

Fang C Mei ◽

Wel Lin ◽

Li Li ◽

...

Keyword(s):

Molecular Mechanism ◽

Stress Responses ◽

Foam Cell ◽

Low Density Lipoprotein ◽

Cellular Stress ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cell Formation ◽

Intracellular Camp ◽

Protein Sumoylation

Protein SUMOylation plays an essential role in maintaining cellular homeostasis when cells are under stress. However, precisely how SUMOylation is regulated, and a molecular mechanism linking cellular stress to SUMOylation remains elusive. Herein, we report that cAMP, a major stress-response second messenger, acts through Epac1 as a regulator of cellular SUMOylation. The Epac1-associated proteome is highly enriched with components of the SUMOylation pathway. Activation of Epac1 by intracellular cAMP triggers phase separation and the formation of nuclear condensates containing Epac1 and general components of the SUMOylation machinery to promote cellular SUMOylation. Furthermore, genetic knockout of Epac1 obliterates oxidized low-density lipoprotein induced cellular SUMOylation in macrophages, leading to suppression of foam cell formation. These results provide a direct nexus connecting two major cellular stress responses to define a molecular mechanism in which cAMP regulates the dynamics of cellular condensates to modulate protein SUMOylation.

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