scholarly journals AGE-RAGE Axis Stimulates Oxidized LDL Uptake into Macrophages through Cyclin-Dependent Kinase 5-CD36 Pathway via Oxidative Stress Generation

2020 ◽  
Vol 21 (23) ◽  
pp. 9263
Author(s):  
Hironori Yashima ◽  
Michishige Terasaki ◽  
Ami Sotokawauchi ◽  
Takanori Matsui ◽  
Yusaku Mori ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Cyclin Dependent Kinase ◽  
Increased Risk ◽  
Ldl Uptake ◽  
Cyclin Dependent Kinase 5 ◽  
Cd36 Gene

Advanced glycation end products (AGEs) are localized in macrophage-derived foam cells within atherosclerotic lesions, which could be associated with the increased risk of atherosclerotic cardiovascular disease under diabetic conditions. Although foam cell formation of macrophages has been shown to be enhanced by AGEs, the underlying molecular mechanism remains unclear. Since cyclin-dependent kinase 5 (Cdk5) is reported to modulate inflammatory responses in macrophages, we investigated whether Cdk5 could be involved in AGE-induced CD36 gene expression and foam cell formation of macrophages. AGEs significantly increased Dil-oxidized low-density lipoprotein (ox-LDL) uptake, and Cdk5 and CD36 gene expression in U937 human macrophages, all of which were inhibited by DNA aptamer raised against RAGE (RAGE-aptamer). Cdk5 and CD36 gene expression levels were correlated with each other. An antioxidant, N-acetyl-l-cysteine, mimicked the effects of RAGE-aptamer on AGE-exposed U937 cells. A selective inhibitor of Cdk5, (R)-DRF053, attenuated the AGE-induced Dil-ox-LDL uptake and CD36 gene expression, whereas anti-CD36 antibody inhibited the Dil-ox-LDL uptake but not Cdk5 gene expression. The present study suggests that AGEs may stimulate ox-LDL uptake into macrophages through the Cdk5–CD36 pathway via RAGE-mediated oxidative stress.

scholarly journals Glucose-Dependent Insulinotropic Polypeptide Suppresses Foam Cell Formation of Macrophages through Inhibition of the Cyclin-Dependent Kinase 5-CD36 Pathway

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 832
Author(s):  
Michishige Terasaki ◽  
Hironori Yashima ◽  
Yusaku Mori ◽  
Tomomi Saito ◽  
Yoshie Shiraga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
U937 Cells ◽  
Cyclin Dependent Kinase ◽  
Macrophage Foam Cell ◽  
Cyclin Dependent Kinase 5 ◽  
Gip Receptor ◽  
Cd36 Gene

Glucose-dependent insulinotropic polypeptide (GIP) has been reported to have an atheroprotective property in animal models. However, the effect of GIP on macrophage foam cell formation, a crucial step of atherosclerosis, remains largely unknown. We investigated the effects of GIP on foam cell formation of, and CD36 expression in, macrophages extracted from GIP receptor-deficient (Gipr−/−) and Gipr+/+ mice and cultured human U937 macrophages by using an agonist for GIP receptor, [D-Ala2]GIP(1–42). Foam cell formation evaluated by esterification of free cholesterol to cholesteryl ester and CD36 gene expression in macrophages isolated from Gipr+/+ mice infused subcutaneously with [D-Ala2]GIP(1–42) were significantly suppressed compared with vehicle-treated mice, while these beneficial effects were not observed in macrophages isolated from Gipr−/− mice infused with [D-Ala2]GIP(1–42). When macrophages were isolated from Gipr+/+ and Gipr−/− mice, and then exposed to [D-Ala2]GIP(1–42), similar results were obtained. [D-Ala2]GIP(1–42) attenuated ox-LDL uptake of, and CD36 gene expression in, human U937 macrophages as well. Gene expression level of cyclin-dependent kinase 5 (Cdk5) was also suppressed by [D-Ala2]GIP(1–42) in U937 cells, which was corelated with that of CD36. A selective inhibitor of Cdk5, (R)-DRF053 mimicked the effects of [D-Ala2]GIP(1–42) in U937 cells. The present study suggests that GIP could inhibit foam cell formation of macrophages by suppressing the Cdk5-CD36 pathway via GIP receptor.

Abstract 356: IKK-Beta Deletion Alleviates the Atherogenetic Effect of Intermittent Hypoxia Induced Macrophage Foam Cell Formation

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Toshihiro Imamura ◽  
Iain S Hartley ◽  
Abdull J Massri ◽  
Orit Poulsen ◽  
Dan Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intermittent Hypoxia ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Wild Type ◽  
Nf Kappa B ◽  
Macrophage Foam Cell ◽  
Obstructive Sleep ◽  
Intracellular Cholesterol

Background: Obstructive sleep apnea syndrome (OSAS) is a common sleeping disorder characterized by intermittent hypoxia (IH). Clinical studies have previously shown an independent association between obstructive sleep apnea and atherosclerosis. Furthermore, it has been previously shown that such a predisposition to atherosclerosis in OSAS patient can be caused by various inflammatory mediators, particularly the NF-kappa B (NF-kB) pathway. Foam cells or lipid-laden macrophages in the atherosclerotic lesion have been well documented as a hallmark of atherosclerosis; however, the contribution of IH, such as in OSAS, to foam cell formation is not yet fully understood. Previous observations have led us to hypothesized that IH induces macrophage foam cell formation due to the activation of NF-kappa B pathway. Methods: Myeloid restricted IKK-beta deleted mice were generated by a Cre/lox recombination system to inactivate the NF-kB pathway in macrophages. Thioglycollate-elicited peritoneal macrophages were incubated with 200 μg/ml of low-density lipoprotein and simultaneously exposed to either IH (Normoxia: 8min, 0.5% O2: 10min) or normoxia for 24 hours. After exposure, the extent of foam cell formation was assessed by quantification of intracellular cholesterol. Finally, we compared the differences in gene expression using RNA-seq between wild type and IKK-beta deleted macrophages exposed to either IH or normoxia for 24 hours. Results: IH significantly increased total cholesterol in wild type macrophages (63.4±3.3 μg/mg of cellular protein, n=9) in comparison to normoxia (51.2±1.6). Interestingly, such increase in intracellular cholesterol in response to IH-exposure was abolished by IKK-beta deletion (IH 52.4±1.1; normoxia 50.0±1.6 n=8), suggesting that NF-kB pathway regulated gene expression is critical for IH-induced foam cell formation. Indeed, we have found that NF-kB knockout abolished IH-induced expressional alterations in 364 genes, which are potential candidates for regulating intracellular cholesterol. Conclusion: NF-kB activation plays a critical role in IH-induced macrophage foam cell formation.

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 Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis

2015 ◽  
Vol 116 (5) ◽  
pp. 789-796 ◽  
Author(s):  
Kevin M. Patel ◽  
Alanna Strong ◽  
Junichiro Tohyama ◽  
Xueting Jin ◽  
Carlos R. Morales ◽  
...  
Keyword(s):  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Ldl Uptake

scholarly journals Determinants of Scavenger Receptor Expression Levels in Human Macrophages

2021 ◽  
Author(s):  
Maile Ralefatane ◽  
Eleanor Cave ◽  
Nigel Crowther
Keyword(s):  
Gene Expression ◽  
Ethnic Groups ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Receptor Expression ◽  
Foam Cell Formation ◽  
Expression Levels

Abstract Background Atherosclerosis involves the accumulation of oxidized low-density lipoprotein (OxLDL)-laden foam cells (FC) within the blood vessel intima. Macrophages are transformed to FCs by the uptake of OxLDL, a process mediated by scavenger receptors (SRs), which include MSR1, CD36 and CD68. Atherosclerosis differs in prevalence across ethnic groups, being less common in African than Indian or European populations. Therefore, our aim was to measure SRs gene expression from macrophages isolated from these three ethnic groups. Methods Ten participants were recruited from each ethnic group (African, European and Indian). Anthropometry and fasting serum lipid and glucose levels were measured. Monocytes were isolated from whole blood and converted to macrophages using standard cell culture procedures. Macrophage RNA was isolated, and reverse transcribed to cDNA. Relative gene expression was calculated using the ∆∆Ct relative quantification method with β-actin used as the normalization control. Multivariable regression analysis was performed to identify the determinants of macrophage SRs expression. Results Expression of the CD36 gene correlated with age (β = 0.33, p = 0.02), LDL (β = 0.29, p = 0.03) and CD68 expression (β = 0.57, p < 0.001). Expression of CD68 correlated with triglycerides (β = 0.45, p = 0.005) and European ethnicity (β = 0.56, p < 0.001). Expression levels of MSR1 correlated positively with LDL (β = 0.27, p = 0.01) and negatively with HDL (β=-0.33, p = 0.003) and African ethnicity (β=-0.73, p < 0.001). Conclusions These data suggest that serum lipids may modulate foam cell formation via effects on macrophage SRs gene expression. Furthermore, ethnic differences in atherosclerotic plaque formation may be mediated through differential CD68 and MSR1 expression levels within macrophages.

scholarly journals A Dipeptidyl Peptidase-4 Inhibitor Inhibits Foam Cell Formation of Macrophages in Type 1 Diabetes via Suppression of CD36 and ACAT-1 Expression

2020 ◽  
Vol 21 (13) ◽  
pp. 4811 ◽  
Author(s):  
Michishige Terasaki ◽  
Hironori Yashima ◽  
Yusaku Mori ◽  
Tomomi Saito ◽  
Takanori Matsui ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Dipeptidyl Peptidase ◽  
Foam Cell Formation ◽  
Dipeptidyl Peptidase 4 ◽  
Harmful Effects

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to play a protective role against atherosclerosis in both animal models and patients with type 2 diabetes (T2D). However, since T2D is associated with dyslipidemia, hypertension and insulin resistance, part of which are ameliorated by DPP-4 inhibitors, it remains unclear whether DPP-4 inhibitors could have anti-atherosclerotic properties directly by attenuating the harmful effects of hyperglycemia. Therefore, we examined whether a DPP-4 inhibitor, teneligliptin, could suppress oxidized low-density lipoprotein (ox-LDL) uptake, foam cell formation, CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) gene expression of macrophages isolated from streptozotocin-induced type 1 diabetes (T1D) mice and T1D patients as well as advanced glycation end product (AGE)-exposed mouse peritoneal macrophages and THP-1 cells. Foam cell formation, CD36 and ACAT-1 gene expression of macrophages derived from T1D mice or patients increased compared with those from non-diabetic controls, all of which were inhibited by 10 nmol/L teneligliptin. AGEs mimicked the effects of T1D; teneligliptin attenuated all the deleterious effects of AGEs in mouse macrophages and THP-1 cells. Our present findings suggest that teneligliptin may inhibit foam cell formation of macrophages in T1D via suppression of CD36 and ACAT-1 gene expression partly by attenuating the harmful effects of AGEs.

scholarly journals Relationship Between Autophagy and Metabolic Syndrome Characteristics in the Pathogenesis of Atherosclerosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Jing Xu ◽  
Munehiro Kitada ◽  
Yoshio Ogura ◽  
Daisuke Koya
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Plaque Rupture ◽  
Cell Formation ◽  
Degradation Process ◽  
Vascular Wall ◽  
Foam Cell Formation ◽  
Plaque Instability

Atherosclerosis is the main cause of mortality in metabolic-related diseases, including cardiovascular disease and type 2 diabetes (T2DM). Atherosclerosis is characterized by lipid accumulation and increased inflammatory cytokines in the vascular wall, endothelial cell and vascular smooth muscle cell dysfunction and foam cell formation initiated by monocytes/macrophages. The characteristics of metabolic syndrome (MetS), including obesity, glucose intolerance, dyslipidemia and hypertension, may activate multiple mechanisms, such as insulin resistance, oxidative stress and inflammatory pathways, thereby contributing to increased risks of developing atherosclerosis and T2DM. Autophagy is a lysosomal degradation process that plays an important role in maintaining cellular metabolic homeostasis. Increasing evidence indicates that impaired autophagy induced by MetS is related to oxidative stress, inflammation, and foam cell formation, further promoting atherosclerosis. Basal and mild adaptive autophagy protect against the progression of atherosclerotic plaques, while excessive autophagy activation leads to cell death, plaque instability or even plaque rupture. Therefore, autophagic homeostasis is essential for the development and outcome of atherosclerosis. Here, we discuss the potential role of autophagy and metabolic syndrome in the pathophysiologic mechanisms of atherosclerosis and potential therapeutic drugs that target these molecular mechanisms.

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