scholarly journals TRAF5 Deficiency Accelerates Atherogenesis in Mice by Increasing Inflammatory Cell Recruitment and Foam Cell Formation

2010 ◽  
Vol 107 (6) ◽  
pp. 757-766 ◽  
Author(s):  
Anna Missiou ◽  
Philipp Rudolf ◽  
Peter Stachon ◽  
Dennis Wolf ◽  
Nerea Varo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Cell ◽  
Foam Cell ◽  
Interleukin 1 ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
High Cholesterol Diet ◽  
Cell Recruitment ◽  
Inflammatory Cell Recruitment

Rationale: Tumor necrosis factor receptor–associated factors (TRAFs) are cytoplasmic adaptor proteins for the TNF/interleukin-1/Toll-like receptor superfamily. Ligands of this family comprise multiple important cytokines such as TNFα, CD40L, and interleukin-1β that promote chronic inflammatory diseases such as atherosclerosis. We recently reported overexpression of TRAF5 in murine and human atheromata and that TRAF5 promotes inflammatory functions of cultured endothelial cells and macrophages. Objective: This study tested the hypothesis that TRAF5 modulates atherogenesis in vivo. Methods and Results: Surprisingly, TRAF5 −/− /LDLR −/− mice consuming a high-cholesterol diet for 18 weeks developed significantly larger atherosclerotic lesions than did TRAF5 +/+ /LDLR −/− controls. Plaques of TRAF5-deficient animals contained more lipids and macrophages, whereas smooth muscle cells and collagen remained unchanged. Deficiency of TRAF5 in endothelial cells or in leukocytes enhanced adhesion of inflammatory cells to the endothelium in dynamic adhesion assays in vitro and in murine vessels imaged by intravital microscopy in vivo. TRAF5 deficiency also increased expression of adhesion molecules and chemokines and potentiated macrophage lipid uptake and foam cell formation. These findings coincided with increased activation of JNK and appeared to be independent of TRAF2. Finally, patients with stable or acute coronary heart disease had significantly lower amounts of TRAF5 mRNA in blood compared with healthy controls. Conclusions: Unexpectedly, TRAF5 deficiency accelerates atherogenesis in mice, an effect likely mediated by increased inflammatory cell recruitment to the vessel wall and enhanced foam cell formation.

scholarly journals Perivascular Adipose Tissue and Vascular Perturbation/Atherosclerosis

2020 ◽  
Vol 40 (11) ◽  
pp. 2569-2576
Author(s):  
Ha Won Kim ◽  
Hong Shi ◽  
Michael A. Winkler ◽  
Richard Lee ◽  
Neal L. Weintraub
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Cell ◽  
Foam Cell ◽  
Inflammatory Cells ◽  
Vasa Vasorum ◽  
Foam Cell Formation ◽  
Adipose Tissues ◽  
Perivascular Adipose Tissue ◽  
Cell Recruitment ◽  
Inflammatory Cell Recruitment

Atherosclerosis is orchestrated by complex interactions between vascular and inflammatory cells. Traditionally, it has been considered to be an intimal inflammatory disease, characterized by endothelial dysfunction, inflammatory cell recruitment, lipid oxidation, and foam cell formation. This inside-out signaling paradigm has been accepted as dogma for many years, despite the fact that inflammatory cells are far more prevalent in the adventitia compared with the intima. For decades, the origin of adventitial inflammation in atherosclerosis was unknown. The fact that these inflammatory cells were observed to cluster at the margin of perivascular adipose tissues—a unique and highly inflammatory adipose depot that surrounds most atherosclerosis-prone blood vessels—has stimulated interest in perivascular adipose tissue–mediated outside-in signaling in vascular pathophysiology, including atherosclerosis. The phenotype of perivascular adipocytes underlies the functional characteristics of this depot, including its role in adventitial inflammatory cell recruitment, trafficking to the intima via the vasa vasorum, and atherosclerosis perturbation. This review is focused on emerging concepts pertaining to outside-in signaling in atherosclerosis driven by dysfunctional perivascular adipose tissues during diet-induced obesity and recent strategies for atherosclerosis prediction and prognostication based upon this hypothesis.

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.

Metformin inhibits monocyte adhesion to endothelial cells and foam cell formation

2003 ◽  
Vol 3 (4) ◽  
pp. 302-310 ◽  
Author(s):  
Jean-Claude Mamputu ◽  
Nicolas Wiernsperger ◽  
Geneviève Renier
Keyword(s):  
Endothelial Cells ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Monocyte Adhesion

Abstract 424: An IFNg-regulated Macrophage Protein Network Links Type 2 Diabetes to Atherosclerosis

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Catherine A Reardon ◽  
Amulya Lingaraju ◽  
Kelly Q Schoenfelt ◽  
Guolin Zhou ◽  
Ning-Chun Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Increased Risk ◽  
Macrophage Dysfunction ◽  
Macrophage Protein

Type 2 diabetics have a higher risk for atherosclerosis, but the mechanisms underlying the increased risk are poorly understood. Macrophages, which are activated in type 2 diabetes (T2D) and have a role in all stages of atherogenesis, are an attractive link. Our hypothesis is that T2D promotes macrophage dysfunction to promote atherosclerosis. To investigate the relationship between T2D and macrophage dysfunction, we used a proteomics approach to identify dysregulated proteins secreted from peritoneal macrophages in a diet induced mouse model of obesity and insulin resistance in the absence of hypercholesterolemia. Twenty-seven T2D responsive proteins were identified that predict defects in many of the critical functions of macrophages in atherosclerosis (e.g. decreased apoE- cholesterol efflux; decreased MFGE8 – efferocytosis, increased MMP12- matrix degradation). The macrophages from lean and obese mice were not lipid loaded, but the obese macrophages accumulated significantly more cholesterol when exposed to high levels of atherogenic lipoproteins in vitro suggesting that dysregulation of the T2D responsive proteins in diabetic mice render macrophages more susceptible to cholesterol loading. Importantly, many of these same protein changes, which were present in atherosclerotic Ldlr-/- mice with T2D, were normalized when these mice were fed non-diabetogenic hypercholesterolemic diets. Thus, foam cell formation in the presence and absence of T2D produces distinct effects on macrophage protein levels, and hence function. Further, we identify IFNγ as a mediator of the T2D responsive protein dysfunction. IFNγ, but not other cytokines, insulin or glucose, promote the T2D responsive protein dysregulation and increased susceptibility to cholesterol accumulation in vitro and the dysregulation is not observed in macrophage foam cells obtained from obese, diabetic IFNγ receptor 1 knockout animals. We also demonstrate that IFNγ can target these proteins in arterial wall macrophages in vivo . These studies suggest that IFNγ is an important mediator of macrophage dysfunction in T2D that may contribute to the enhanced cardiovascular risk in these patients.

scholarly journals A Growth Hormone-Releasing Peptide Promotes Mitochondrial Biogenesis and a Fat Burning-Like Phenotype through Scavenger Receptor CD36 in White Adipocytes

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1009-1018 ◽  
Author(s):  
Amélie Rodrigue-Way ◽  
Annie Demers ◽  
Huy Ong ◽  
André Tremblay
Keyword(s):  
Mitochondrial Biogenesis ◽  
Foam Cell ◽  
Uncoupling Protein ◽  
Scavenger Receptor ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Ppar Γ ◽  
Cd36 Expression ◽  
White Fat

Whereas the uptake of oxidized lipoproteins by scavenger receptor CD36 in macrophages has been associated with foam cell formation and atherogenesis, little is known about the role of CD36 in regulating lipid metabolism in adipocytes. Here we report that treatment of 3T3-L1 adipocytes with hexarelin, a GH-releasing peptide that interacts with CD36, resulted in a depletion of intracellular lipid content with no significant change in CD36 expression. Microarray analysis revealed an increased pattern in several genes involved in fatty acid mobilization toward the mitochondrial oxidative phosphorylation process in response to hexarelin. Interestingly, many of these up-regulated genes are known targets of peroxisomal proliferator-activated receptor (PPAR)-γ, such as FATP, CPT-1, and F1-ATPase, suggesting that adipocyte response to hexarelin may involve PPARγ activation. Expression studies also indicate an increase in thermogenic markers PPARγ coactivator 1α and uncoupling protein-1, which are normally expressed in brown adipocytes. Electron microscopy of hexarelin-treated 3T3-L1 adipocytes showed an intense and highly organized cristae formation that spans the entire width of mitochondria, compared with untreated cells, and cytochrome c oxidase activity was enhanced by hexarelin, two features characteristic of highly oxidative tissues. A similar mitochondrial phenotype was detected in epididymal white fat of mice treated with hexarelin, along with an increased expression of thermogenic markers that was lost in treated CD36-null mice, suggesting that the ability of hexarelin to promote a brown fat-like phenotype also occurs in vivo and is dependent on CD36. These results provide a potential role for CD36 to impact the overall metabolic activity of fat usage and mitochondrial biogenesis in adipocytes.

Foam cell formation in vivo is pro-fibrotic

2015 ◽  
Vol 241 (1) ◽  
pp. e81-e82 ◽  
Author(s):  
A. Newby ◽  
A. Thomas
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation

scholarly journals 11β-Hydroxysteroid Dehydrogenase Type 1 Gene Knockout Attenuates Atherosclerosis and In Vivo Foam Cell Formation in Hyperlipidemic apoE−/− Mice

PLoS ONE ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. e53192 ◽  
Author(s):  
Ricardo A. García ◽  
Debra J. Search ◽  
John A. Lupisella ◽  
Jacek Ostrowski ◽  
Bo Guan ◽  
...  
Keyword(s):  
Foam Cell ◽  
Gene Knockout ◽  
Cell Formation ◽  
Hydroxysteroid Dehydrogenase ◽  
Foam Cell Formation

scholarly journals ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation

2012 ◽  
Vol 209 (4) ◽  
pp. 807-817 ◽  
Author(s):  
Elizabeth S. Gold ◽  
Stephen A. Ramsey ◽  
Mark J. Sartain ◽  
Jyrki Selinummi ◽  
Irina Podolsky ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Lipid Body ◽  
Chronic Inflammatory Disease ◽  
Intersection Point ◽  
Prediction Algorithm ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Body Formation

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. We demonstrate that macrophage lipid body formation can be induced by modified lipoproteins or by inflammatory Toll-like receptor agonists. We used an unbiased approach to study the overlap in these pathways to identify regulators that control foam cell formation and atherogenesis. An analysis method integrating epigenomic and transcriptomic datasets with a transcription factor (TF) binding site prediction algorithm suggested that the TF ATF3 may regulate macrophage foam cell formation. Indeed, we found that deletion of this TF results in increased lipid body accumulation, and that ATF3 directly regulates transcription of the gene encoding cholesterol 25-hydroxylase. We further showed that production of 25-hydroxycholesterol (25-HC) promotes macrophage foam cell formation. Finally, deletion of ATF3 in Apoe−/− mice led to in vivo increases in foam cell formation, aortic 25-HC levels, and disease progression. These results define a previously unknown role for ATF3 in controlling macrophage lipid metabolism and demonstrate that ATF3 is a key intersection point for lipid metabolic and inflammatory pathways in these cells.

scholarly journals The extracellular matrix protein mindin serves as an integrin ligand and is critical for inflammatory cell recruitment

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3854-3859 ◽  
Author(s):  
Wei Jia ◽  
Hong Li ◽  
You-Wen He
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Inflammatory Cell ◽  
Neutrophil Migration ◽  
Extracellular Matrix Protein ◽  
Hek 293 ◽  
Cell Recruitment ◽  
Inflammatory Cell Recruitment

Leukocyte recruitment to inflammation sites depends on interactions between integrins and extracellular matrix (ECM). In this report we show that mice lacking the ECM protein mindin exhibit severely impaired recruitment of neutrophils and macrophages in 4 different inflammation models. Furthermore, neutrophils directly bind to immobilized mindin, and mindin matrix mediates neutrophil migration in vitro. The adhesion of neutrophils to mindin is blocked by anti–integrin α4, anti–integrin αM, and anti–integrin β2 antibodies. We also show that HEK-293 cells transfected with cDNA encoding these integrins exhibit enhanced binding to immobilized mindin matrix and the increased binding can be blocked by anti-integrin antibodies. Our results suggest that mindin serves as a novel ligand for integrins and mindin-integrin interactions are critical for inflammatory cell recruitment in vivo.

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