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 Modeling early stage atherosclerosis in a primary human vascular microphysiological system

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xu Zhang ◽  
Muath Bishawi ◽  
Ge Zhang ◽  
Varun Prasad ◽  
Ellen Salmon ◽  
...  
Keyword(s):  
Cell Activation ◽  
Foam Cell ◽  
Early Stage ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
No Production ◽  
Endothelial Cell Activation

Abstract Novel atherosclerosis models are needed to guide clinical therapy. Here, we report an in vitro model of early atherosclerosis by fabricating and perfusing multi-layer arteriole-scale human tissue-engineered blood vessels (TEBVs) by plastic compression. TEBVs maintain mechanical strength, vasoactivity, and nitric oxide (NO) production for at least 4 weeks. Perfusion of TEBVs at a physiological shear stress with enzyme-modified low-density-lipoprotein (eLDL) with or without TNFα promotes monocyte accumulation, reduces vasoactivity, alters NO production, which leads to endothelial cell activation, monocyte accumulation, foam cell formation and expression of pro-inflammatory cytokines. Removing eLDL leads to recovery of vasoactivity, but not loss of foam cells or recovery of permeability, while pretreatment with lovastatin or the P2Y11 inhibitor NF157 reduces monocyte accumulation and blocks foam cell formation. Perfusion with blood leads to increased monocyte adhesion. This atherosclerosis model can identify the role of drugs on specific vascular functions that cannot be assessed in vivo.

Abstract 659: Macrophage Beta3 Integrin Deficiency Promotes Atherosclerosis Development Through ERK-Dependent Signaling

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Cristina Wolf ◽  
Ellen Damm ◽  
Berend Isermann ◽  
Clay Semenkovich ◽  
Katherine Weilbaecher ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Signaling Mechanism ◽  
Tissue Specific ◽  
Β3 Integrin ◽  
Specific Deletion

Atherosclerosis is a chronic inflammation of the arterial wall caused by accumulation of cholesterol. This complex process involves endothelial and smooth muscle cells as well as the recruitment and differentiation of circulating monocytes. Integrins are membrane-bound molecules that are involved in signaling between cells and the extracellular matrix, thereby influencing intracellular signaling and cytoskeletal stability. We and others have described the in vivo consequences of germline deletion of the β3 integrin in inflammation, atherosclerosis and cancer. However, the distinct pathophysiological consequences of its tissue-specific deletion in macrophage function in development of atherosclerotic lesions remain mostly elusive. Our aim was to characterize for the first time the phenotype of mice with tissue-specific deletion of β3 integrin in macrophages (LyzMCre) under high fat diet (HFD) condition on atherosclerotic prone backgrounds (ApoE-/- and LDLr-/-), and to elucidate the signaling mechanism involved using in vitro methods. Tissue specific β3 integrin deficiency in macrophages alone is sufficient to cause increased lesion formation in the aorta of mice on HFD on both backgrounds used suggesting an important atheroprotective role played by this integrin. β3 integrin-deficient bone marrow-derived macrophages (BMDM) treated with oxLDL in vitro demonstrated a strong cholesterol uptake and increased foam cell formation. We identified that β3 integrin deficiency in macrophages caused an early activation of Ras followed by ERK phosphorylation, deficient cholesterol efflux and decreased expression of cholesterol transporter (ABCA1) which is a major regulator of cellular cholesterol. Inhibition of the ERK pathway reduced foam cell formation of macrophages at least partially by restoring expression of ABCA1. Taken together, our results show that macrophage β3 integrin is an important signaling molecule for cellular activation. Its deficiency showed important functional consequences in regard to inflammation and atherosclerosis that could be possibly modulated by interfering with downstream signaling.

The Role of Microscopy in Understanding Atherosclerotic Lysosomal Lipid Metabolism

2003 ◽  
Vol 9 (1) ◽  
pp. 54-67 ◽  
Author(s):  
W. Gray Jerome ◽  
Patricia G. Yancey
Keyword(s):  
Cultured Cells ◽  
Foam Cell ◽  
Critical Role ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Cholesteryl Esters ◽  
Normal Metabolism

Microscopy has played a critical role in first identifying and then defining the role of lysosomes in formation of atherosclerotic foam cells. We review the evidence implicating lysosomal lipid accumulation as a factor in the pathogenesis of atherosclerosis with reference to the role of microscopy. In addition, we explore mechanisms by which lysosomal lipid engorgement occurs. Low density lipoproteins which have become modified are the major source of lipid for foam cell formation. These altered lipoproteins are taken into the cell via receptor-mediated endocytosis and delivered to lysosomes. Under normal conditions, lipids from these lipoproteins are metabolized and do not accumulate in lysosomes. In the atherosclerotic foam cell, this normal metabolism is inhibited so that cholesterol and cholesteryl esters accumulate in lysosomes. Studies of cultured cells incubated with modified lipoproteins suggests this abnormal metabolism occurs in two steps. Initially, hydrolysis of lipoprotein cholesteryl esters occurs normally, but the resultant free cholesterol cannot exit the lysosome. Further lysosomal cholesterol accumulation inhibits hydrolysis, producing a mixture of cholesterol and cholesteryl esters within swollen lysosomes. Various lipoprotein modifications can produce this lysosomal engorgement in vitro and it remains to be seen which modifications are most important in vivo.

scholarly journals Pomegranate Protection against Cardiovascular Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-20 ◽  
Author(s):  
Michael Aviram ◽  
Mira Rosenblat
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Pomegranate Juice ◽  
Foam Cell Formation ◽  
Atherosclerosis Development ◽  
By Products ◽  
Lipids Accumulation

The current paper summarizes the antioxidative and antiatherogenic effects of pomegranate polyphenols on serum lipoproteins and on arterial macrophages (two major components of the atherosclerotic lesion), using bothin vitroandin vivohumans and mice models. Pomegranate juice and its by-products substantially reduced macrophage cholesterol and oxidized lipids accumulation, and foam cell formation (the hallmark of early atherogenesis), leading to attenuation of atherosclerosis development, and its consequent cardiovascular events.

scholarly journals TLR4-dependent signaling drives extracellular catabolism of low-density lipoprotein aggregates

2019 ◽  
Author(s):  
Rajesh K. Singh ◽  
Abigail S. Haka ◽  
Arky Asmal ◽  
Valéria C. Barbosa-Lorenzi ◽  
Inna Grosheva ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Lipid Accumulation ◽  
Foam Cell ◽  
Cell Formation ◽  
Adaptor Protein ◽  
Foam Cell Formation ◽  
Low Density

ABSTRACTObjectiveAggregation and modification of low-density lipoproteins (LDL) promotes their retention and accumulation in the arteries. This is a critical initiating factor during atherosclerosis. Macrophage catabolism of aggregated LDL (agLDL) occurs using a specialized extracellular, hydrolytic compartment, the lysosomal synapse (LS). Compartment formation by local actin polymerization and delivery of lysosomal contents by exocytosis promotes acidification of the compartment and degradation of agLDL. Internalization of metabolites such as cholesterol promotes foam cell formation, a process that drives atherogenesis. Further, there is accumulating evidence for the involvement of TLR4 and its adaptor protein MyD88 in atherosclerosis. Here, we investigated the role of TLR4 in catabolism of agLDL using the LS and foam cell formation.Approach and ResultsUsing bone marrow-derived macrophages (BMMs) from knockout mice, we find that TLR4 and MyD88 regulate compartment formation, lysosome exocytosis, acidification of the compartment and foam cell formation. Using siRNA, pharmacological inhibition and knockout BMMs, we implicate SYK, PI3 kinase and Akt in agLDL catabolism using the LS. Using bone marrow transplantation of LDL receptor knockout mice with TLR4KO bone marrow, we show that deficiency of TLR4 protects macrophages from lipid accumulation during atherosclerosis. Finally, we demonstrate that macrophages in vivo form an extracellular compartment and exocytose lysosome contents similar to that observed in vitro for degradation of agLDL.ConclusionsWe present a mechanism in which interaction of macrophages with agLDL initiates a TLR4 signaling pathway, resulting in formation of the LS, catabolism of agLDL and lipid accumulation in vitro and in vivo.

Metformin Inhibits N-Methyl-N-Nitrosourea Induced Gastric Tumorigenesis in db/db Mice

2017 ◽  
Vol 125 (06) ◽  
pp. 392-399 ◽  
Author(s):  
Shan Zhuang ◽  
Yongmei Jian ◽  
Yongning Sun
Keyword(s):  
Gastric Cancer ◽  
Type 2 Diabetes ◽  
Inflammatory Cytokines ◽  
Serum Insulin ◽  
Inhibitory Effect ◽  
Increased Risk ◽  
Pro Inflammatory Cytokines

Abstract Type 2 diabetes can elevate risk of gastric cancer and metformin, an anti-diabetic agent, has an inhibitory effect against gastric cancer cell in vitro. However, the effect of metformin on type 2 diabetes-related gastric tumorigenesis in vivo is still not clear. In the present study, we aim to detect whether metformin can inhibit increased risk of gastric cancer in diabetic db/db mice and which the potential anti-cancer mechanisms of metformin are. 4-week-old mice were divided into 3 groups (2 db/db mice groups and one wild type mice group). All diabetic and non-diabetic mice were treated with N-Methyl-N-Nitrosourea (MNU) for 20 weeks to induce gastric tumorigenesis. At week 21, one db/db mice group were treated with metformin (5 mg/ml) for 10 weeks and the other 2 groups were treated with saline. Blood samples were collected for testing insulin and insulin-like growth factor (IGF)-1. Stomach tissues were collected for histopathological evaluation and mRNAs analysis. Metformin significantly decreased incidence of MNU-induced gastric dysplasia and cancer in diabetic db/db mice. Furthermore, metformin reduced serum insulin as well as IGF-1, and also suppressed expression of insulin receptor, IGF-1, IGF-1 receptor and several pro-inflammatory cytokines mRNAs in stomach of db/db mice, but did not significantly influence IGF-2 and IGF-2 receptor expressions. The results show that metformin can prevent the risk of gastric cancer in type 2 diabetes and the protective mechanisms may involve in an inhibitory effect of metformin on insulin as well as IGF-1 signals and cancer related pro-inflammatory cytokines.

ApoE-mediated cholesterol efflux from macrophages: separation of autocrine and paracrine effects

2005 ◽  
Vol 288 (3) ◽  
pp. C586-C592 ◽  
Author(s):  
Dwayne E. Dove ◽  
MacRae F. Linton ◽  
Sergio Fazio
Keyword(s):  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
The Novel ◽  
Paracrine Effects ◽  
Paracrine Effect ◽  
Signal Transduction Systems

Macrophages in the vessel wall secrete high levels of apolipoprotein E (apoE). Cholesterol efflux from macrophages to apoE has been shown to decrease foam cell formation and prevent atherosclerosis. An apoE molecule can mediate cholesterol efflux from the macrophage that originally secreted it (autocrine effect) or from surrounding macrophages (paracrine effect). Traditional methodologies have not been able to separate these serial effects. The novel methodology presented here was developed to separate autocrine and paracrine effects by using a simple mathematical model to interpret the effects of dilution on apoE-mediated cholesterol efflux. Our results show that, at very dilute concentrations, the paracrine effect of apoE is not evident and the autocrine effect becomes the dominant mediator of efflux. However, at saturating concentrations, paracrine apoE causes 80–90% of the apoE-mediated cholesterol efflux, whereas autocrine apoE is responsible for the remaining 10–20%. These results suggest that the relative importance of autocrine and paracrine apoE depends on the size of the local distribution volume, a factor not considered in previous in vitro studies of apoE function. Furthermore, autocrine effects of apoE could be critical in the prevention of foam cell formation in vivo. This novel methodology may be applicable to other types of mixed autocrine/paracrine systems, such as signal transduction systems.

scholarly journals A Dipeptidyl Peptidase-4 Inhibitor Suppresses Macrophage Foam Cell Formation in Diabetic db/db Mice and Type 2 Diabetes Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Michishige Terasaki ◽  
Munenori Hiromura ◽  
Yusaku Mori ◽  
Kyoko Kohashi ◽  
Hideki Kushima ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Foam Cell ◽  
Ex Vivo ◽  
Cell Formation ◽  
Dipeptidyl Peptidase ◽  
Foam Cell Formation ◽  
Dipeptidyl Peptidase 4 ◽  
Gene Expression Levels

Dipeptidyl peptidase-4 (DPP-4) inhibitors could have antiatherosclerotic action, in addition to antihyperglycemic roles. Because macrophage foam cells are key components of atherosclerosis, we investigated the effect of the DPP-4 inhibitor teneligliptin on foam cell formation and its related gene expression levels in macrophages extracted from diabetic db/db (C57BLKS/J Iar -+Leprdb/+Leprdb) mice and type 2 diabetes (T2D) patients ex vivo. We incubated mouse peritoneal macrophages and human monocyte-derived macrophages differentiated by 7-day culture with oxidized low-density lipoprotein in the presence/absence of teneligliptin (10 nmol/L) for 18 hours. We observed remarkable suppression of foam cell formation by teneligliptin treatment ex vivo in macrophages isolated from diabetic db/db mice (32%) and T2D patients (38%); this effect was accompanied by a reduction of CD36 (db/db mice, 43%; T2D patients, 46%) and acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) gene expression levels (db/db mice, 47%; T2D patients, 45%). Molecular mechanisms underlying this effect are associated with downregulation of CD36 and ACAT-1 by teneligliptin. The suppressive effect of a DPP-4 inhibitor on foam cell formation in T2D is conserved across species and is worth studying to elucidate its potential as an intervention for antiatherogenesis in T2D patients.

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