scholarly journals The Potential Role of Electronegative High-Density Lipoprotein H5 Subfraction in RA-Related Atherosclerosis

2021 ◽  
Vol 22 (21) ◽  
pp. 11419
Author(s):  
Ching-Kun Chang ◽  
Wei-Chung Cheng ◽  
Wen-Lung Ma ◽  
Po-Ku Chen ◽  
Chu-Huang Chen ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Foam Cell ◽  
Subclinical Atherosclerosis ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
High Density ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Mrna And Protein Expression

Although the heterogeneity of high-density lipoprotein-cholesterol (HDL-c) composition is associated with atherosclerotic cardiovascular risk, the link between electronegative subfractions of HDL-c and atherosclerosis in rheumatoid arthritis (RA) remains unknown. We examined the association of the percentage of the most electronegative subfraction of HDL-c (H5%) and RA-related atherosclerosis. Using anion-exchange purification/fast-protein liquid chromatography, we demonstrated significantly higher H5% in patients (median, 7.2%) than HC (2.8%, p < 0.005). Multivariable regression analysis revealed H5% as a significant predictor for subclinical atherosclerosis. We subsequently explored atherogenic role of H5 using cell-based assay. The results showed significantly higher levels of IL-1β and IL-8 mRNA in H5-treated (mean ± SD, 4.45 ± 1.22 folds, 6.02 ± 1.43-folds, respectively) than H1-treated monocytes (0.89 ± 0.18-folds, 1.03 ± 0.26-folds, respectively, both p < 0.001). In macrophages, H5 upregulated the mRNA and protein expression of IL-1β and IL-8 in a dose-dependent manner, and their expression levels were significantly higher than H1-treated macrophages (all p < 0.001). H5 induced more foam cell formation compared with H1-treated macrophages (p < 0.005). In addition, H5 has significantly lower cholesterol efflux capacity than H1 (p < 0.005). The results of nanoLC-MS/MS approach reveal that the best discriminator between high-H5% and normal-H5% is Apo(a), the main constituent of Lp(a). Moreover, Lp(a) level is a significant predictor for high-H5%. These observations suggest that H5 is involved in RA-related atherosclerosis.

scholarly journals Structure and Dynamics of Oxidized Lipoproteins In Vivo: Roles of High-Density Lipoprotein

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 655
Author(s):  
Hiroyuki Itabe ◽  
Naoko Sawada ◽  
Tomohiko Makiyama ◽  
Takashi Obama
Keyword(s):  
Cardiovascular Diseases ◽  
High Density Lipoprotein ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
High Density ◽  
Oxidative Modification ◽  
Foam Cell Formation ◽  
Oxidized Lipoproteins

Oxidative modification of lipoproteins is implicated in the occurrence and development of atherosclerotic lesions. Earlier studies have elucidated on the mechanisms of foam cell formation and lipid accumulation in these lesions, which is mediated by scavenger receptor-mediated endocytosis of oxidized low-density lipoprotein (oxLDL). Mounting clinical evidence has supported the involvement of oxLDL in cardiovascular diseases. High-density lipoprotein (HDL) is known as anti-atherogenic; however, recent studies have shown circulating oxidized HDL (oxHDL) is related to cardiovascular diseases. A modified structure of oxLDL, which was increased in the plasma of patients with acute myocardial infarction, was characterized. It had two unique features: (1) a fraction of oxLDL accompanied oxHDL, and (2) apoA1 was heavily modified, while modification of apoB, and the accumulation of oxidized phosphatidylcholine (oxPC) and lysophosphatidylcholine (lysoPC) was less pronounced. When LDL and HDL were present at the same time, oxidized lipoproteins actively interacted with each other, and oxPC and lysoPC were transferred to another lipoprotein particle and enzymatically metabolized rapidly. This brief review provides a novel view on the dynamics of oxLDL and oxHDL in circulation.

scholarly journals High-density lipoprotein or cyclodextrin extraction of cholesterol from aggregated LDL reduces foam cell formation

2019 ◽  
Vol 132 (23) ◽  
pp. jcs237271 ◽  
Author(s):  
Rajesh K. Singh ◽  
Frederik W. Lund ◽  
Abigail S. Haka ◽  
Frederick R. Maxfield
Keyword(s):  
High Density Lipoprotein ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
High Density ◽  
Foam Cell Formation

scholarly journals Dysfunctional high-density lipoprotein from HIV+ individuals promotes monocyte-derived foam cell formation in vitro

AIDS ◽  
2017 ◽  
Vol 31 (17) ◽  
pp. 2331-2336 ◽  
Author(s):  
Thomas A. Angelovich ◽  
Anna C. Hearps ◽  
Michael N. Oda ◽  
Mark S. Borja ◽  
Diana Huynh ◽  
...  
Keyword(s):  
High Density Lipoprotein ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
High Density ◽  
Foam Cell Formation

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 TRPM2 deficiency protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages

2021 ◽  
Author(s):  
Pengyu Zong ◽  
Jianlin Feng ◽  
Zhichao Yue ◽  
Albert S. Yu ◽  
Yasuo Mori ◽  
...  
Keyword(s):  
Foam Cell ◽  
Heart Diseases ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Macrophage Infiltration ◽  
Plaque Burden ◽  
Foam Cell Formation ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Monocyte Chemoattractant Protein 1

Atherosclerosis is the major cause of ischemic heart diseases and ischemic brain stroke, which are the leading causes of mortality worldwide. The central pathological features of atherosclerosis include macrophage infiltration and foam cell formation. However, the detailed mechanisms regulating these two processes remain unclear. Here we show that oxidative stress-activated Ca2+-permeable TRPM2 plays a key role in the pathogenesis of atherosclerosis. Trpm2 deletion produces a potent protective effect against atherosclerosis in ApoE-/- mice fed with a high-fat diet (HFD), as evidenced by reduced atherosclerotic plaque burden, decreased macrophage load and suppressed inflammasome activation in the vessel wall. Moreover, we show that Trpm2 deletion or inhibition reduces oxidized low-density lipoprotein (oxLDL) uptake by macrophages, suppresses macrophage infiltration induced by monocyte chemoattractant protein-1 (MCP1), and prevents the impairment of macrophage emigration caused by oxLDL. Intriguingly, we uncover that activation of CD36, an oxLDL receptor, can promote the activation of TRPM2, and vice versa, the CD36-mediated inflammatory cascade in atherosclerosis is dependent on TRPM2. In transfected HEK293T cells, CD36 ligands oxLDL and TSP1 induce TRPM2 activation in a CD36-dependent manner. Deleting Trpm2 or inhibiting TRPM2 activity in cultured macrophages suppresses the CD36 signaling cascade induced by oxLDL and TSP1. Our studies establish TRPM2-CD36 axis as a new mechanism underlying atherogenesis, and suggest TRPM2 as an effective therapeutic target for atherosclerosis.

Abstract 442: D-4F, an Apolipoprotein A-I Mimetic Peptide, Protects Macrophages From Oxidized Low-Density Lipoprotein--Induced Apoptosis by Inhibiting the Endoplasmic Reticulum Stress-C/EBP Homologous Protein Pathway

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Shutong Yao ◽  
Hua Tian ◽  
Cheng Miao ◽  
Li Zhao ◽  
Peng Jiao ◽  
...  
Keyword(s):  
Er Stress ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Homologous Protein ◽  
Raw264.7 Macrophages ◽  
Induced Apoptosis

Objective: D-4F, an apolipoprotein A-I (apoA-I) mimetic peptide, exerts a variety of atheroprotective functions similar to apoA-I, the major protein component of high density lipoprotein (HDL), including acting as an antioxidant, mediating cholesterol efflux from foam cells and direct anti-inflammatory effects. Our previous studies have demonstrated that endoplasmic reticulum (ER) stress promotes macrophage-derived foam cell formation by upregulating CD36 expression and mediates oxidized low-density lipoprotein (ox-LDL)-induced macrophage apoptosis. The goal of this study was to investigate the protective effect of D-4F on ox-LDL-induced macrophage cytotoxicity and specifically the ER stress-C/EBP homologous protein (CHOP) pathway-mediated apoptosis. Methods and Results: Treatment with D-4F (12.5, 25 and 50 mg/L) attenuated ox-LDL (100 mg/L)-induced cholesterol accumulation in RAW264.7 macrophages and foam cell formation in a dose-dependent manner. Similar to tunicamycin (TM), a classical ER stress inducer, ox-LDL reduced cell viability and induced apoptosis in RAW264.7 macrophages. The cytotoxic effects of ox-LDL (100 mg/L) and TM (5 mg/L) were remarkably inhibited by D-4F treatment. Interestingly, we found that D-4F also significantly suppressed the ox-LDL- and TM-induced CD36 upregulation and activation of ER stress signaling events, including the phosphorylation of inositol-requiring enzyme 1 (IRE1) and nuclear translocation of activating transcription factor 6 (ATF6). In addition, exposure of RAW264.7 macrophages to ox-LDL or TM resulted in a significant increase in the expression of CHOP, a proapoptotic transcription factor regulated by IRE1 and ATF6 under conditions of ER stress. D-4F blocked these effects in a dose-dependent manner. Moreover, administration of apoE –/– mice with D-4F (1 mg/kg per day) suppressed apoptosis and the upregulation of CD36, phospho-IRE1, GRP78 and CHOP in macrophage-dense atherosclerotic lesions. Conclusion: These data indicate that D-4F can protect macrophages from ox-LDL-induced apoptosis and that the mechanism at least partially involves its ability to inhibit the ER stress-CHOP signaling pathway.

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 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.

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