GENE EXPRESSION ANALYSIS TO IDENTIFY GENES INVOLVED IN INFLAMMATORY RESPONSES DURING FOAM CELL FORMATION

2004 ◽  
Vol 13 (3) ◽  
pp. 25
Author(s):  
Mathijs Groeneweg ◽  
Menno de Winther ◽  
Marten Hofker
Keyword(s):  
Gene Expression ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation

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.

Inhibitory effects of vasostatin-1 against atherogenesis

2018 ◽  
Vol 132 (23) ◽  
pp. 2493-2507 ◽  
Author(s):  
Yuki Sato ◽  
Rena Watanabe ◽  
Nozomi Uchiyama ◽  
Nana Ozawa ◽  
Yui Takahashi ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Inhibitory Effects ◽  
Macrophage Foam Cell ◽  
Down Regulation ◽  
Atherosclerotic Lesions

Vasostatin-1, a chromogranin A (CgA)-derived peptide (76 amino acids), is known to suppress vasoconstriction and angiogenesis. A recent study has shown that vasostatin-1 suppresses the adhesion of human U937 monocytes to human endothelial cells (HECs) via adhesion molecule down-regulation. The present study evaluated the expression of vasostatin-1 in human atherosclerotic lesions and its effects on inflammatory responses in HECs and human THP-1 monocyte-derived macrophages, macrophage foam cell formation, migration and proliferation of human aortic smooth muscle cells (HASMCs) and extracellular matrix (ECM) production by HASMCs, and atherogenesis in apolipoprotein E-deficient (ApoE−/−) mice. Vasostatin-1 was expressed around Monckeberg’s medial calcific sclerosis in human radial arteries. Vasostatin-1 suppressed lipopolysaccharide (LPS)-induced up-regulation of monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in HECs. Vasostatin-1 suppressed inflammatory M1 phenotype and LPS-induced interleukin-6 (IL-6) secretion via nuclear factor-κB (NF-κB) down-regulation in macrophages. Vasostatin-1 suppressed oxidized low-density lipoprotein (oxLDL)-induced foam cell formation associated with acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) and CD36 down-regulation and ATP-binding cassette transporter A1 (ABCA1) up-regulation in macrophages. In HASMCs, vasostatin-1 suppressed angiotensin II (AngII)-induced migration and collagen-3 and fibronectin expression via decreasing ERK1/2 and p38 phosphorylation, but increased elastin expression and matrix metalloproteinase (MMP)-2 and MMP-9 activities via increasing Akt and JNK phosphorylation. Vasostatin-1 did not affect the proliferation and apoptosis in HASMCs. Four-week infusion of vasostatin-1 suppressed the development of aortic atherosclerotic lesions with reductions in intra-plaque inflammation, macrophage infiltration, and SMC content, and plasma glucose level in ApoE−/− mice. These results indicate the inhibitory effects of vasostatin-1 against atherogenesis. The present study provided the first evidence that vasostatin-1 may serve as a novel therapeutic target for atherosclerosis.

Abstract 249: Increased Vascular CCRL2 Expression by Disturbed Blood Flow Promotes Atherosclerotic Plaque Formation in ApoE Deficient Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Shuhong Hu ◽  
Li Zhu
Keyword(s):  
Blood Flow ◽  
Atherosclerotic Plaque ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Vascular Wall ◽  
Chronic Inflammatory Disease ◽  
Plaque Formation ◽  
Foam Cell Formation ◽  
Cell Trafficking

Atherosclerosis is a chronic inflammatory disease of the arterial wall elicited by accumulation of LDL and leucocytes in the subendothelium at predilection sites with disturbed laminar flow. Chemokines and their receptors appear to act as critical players in atherosclerosis as they not only direct atherogenic recruitment of leucocytes but also exert cell hemostatic functions by chemokine ligand-receptor axes and their specific or combined contributions. Atypical chemokine (C-C motif) receptor-like 2 (CCRL2) cooperates with its ligand chemerin and leukocyte-expressed chemerin receptor chemokine-like receptor 1 (CMKLR1) to regulate cell trafficking and inflammatory responses,but its role in atherosclerosis is not clear. To investigate whether CCRL2 contributes to the pathomechanism of atherogenesis, we generated CCRL2 -/- mice in hyperlipidemic atherosclerosis-prone ApoE -/- background and found that the atherosclerotic plaque area of the total aorta was significantly reduced compared with CCRL2 +/+ ApoE -/- mice on a high fat diet. The protective effect of CCRL2 deficiency was anatomically isolated primarily to the site of disturbed blood flow (D-flow) in the aortic arch but not in the descending aorta. Endothelial CCRL2 was upregulated in response to D-flow and either CCRL2 or CMKLR1 deletion reduced plaque formation. Further studies showed that CCRL2 co-localized with CMKLR1 and chemerin within the atherosclerotic aorta root. CCRL2 deficiency led to significantly less lipid deposition in aortic root, reduced CMKLR1 + leukocyte rolling on lesional vascular endothelium, diminished macrophage accumulation and foam cell formation, and polarized macrophage to an M2-like phenotype. These results demonstrate that D-flow induction of vascular CCRL2 is required for optimal formation of atherosclerotic plaques via coordinating the accumulation of CMKLR1 + monocytes/macrophages within the vascular wall, and thus identifies CCRL2 as a novel drug target to prevent or treat atherosclerosis. This work was supported by Natural Science Foundation of China (grant 81370373 to L.Z. and 31300781 to C.T.) Key Words: atherosclerosis, CCRL2, chemerin, macrophage

NUMERICAL MODELING OF ATHEROSCLEROSIS LESION EVOLUTION IN TIME I. INITIAL STAGE OF THE DISEASE

2016 ◽  
Vol 16 (05) ◽  
pp. 1650068
Author(s):  
SAFOORA KARIMI ◽  
MITRA DADVAR ◽  
BAHRAM DABIR
Keyword(s):  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Ldl Oxidation ◽  
Foam Cell Formation ◽  
Type I ◽  
Specific Patient ◽  
Disease Evolution ◽  
Endothelium Dysfunction ◽  
Initial Stage

Atherosclerosis is one of the main causes of death in the developed world. The disease, which is an inflammatory disease, has been the focus of many studies. A few studies attempted to model atherosclerosis lesion development mathematically while no attention has been paid to the multistage nature of the disease. The present study provides a mathematical model for atherosclerosis evolution by focusing on the inflammatory responses of the initial stage of the disease. In the model, the inflammatory response in type I lesion, which includes endothelium dysfunction, LDL oxidation, monocytes entry, foam cell formation and intima property changes, are coupled with the transport equations of blood and LDL in lumen and arterial wall. The innovation of the model is determination of the duration of the initial stage of lesion propagation for a specific patient while the presence of leaky junction in endothelial layer and LDL oxidation in the intima layer are considered. The greatest advantage of the study in comparison with previous studies is to provide a model for the initiating stage of the atherosclerosis development so that a more precise result of the disease evolution is obtained.

scholarly journals Neutrophils as a Novel Target of Modified Low-Density Lipoproteins and an Accelerator of Cardiovascular Diseases

2020 ◽  
Vol 21 (21) ◽  
pp. 8312
Author(s):  
Takashi Obama ◽  
Hiroyuki Itabe
Keyword(s):  
Cardiovascular Diseases ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Vascular Endothelial Cells ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Foam Cell Formation ◽  
Low Density

Neutrophil extracellular traps (NETs) significantly contribute to various pathophysiological conditions, including cardiovascular diseases. NET formation in the vasculature exhibits inflammatory and thrombogenic activities on the endothelium. NETs are induced by various stimulants such as exogenous damage-associated molecular patterns (DAMPs). Oxidatively modified low-density lipoprotein (oxLDL) has been physiologically defined as a subpopulation of LDL that comprises various oxidative modifications in the protein components and oxidized lipids, which could act as DAMPs. oxLDL has been recognized as a crucial initiator and accelerator of atherosclerosis through foam cell formation by macrophages; however, recent studies have demonstrated that oxLDL stimulates neutrophils to induce NET formation and enhance NET-mediated inflammatory responses in vascular endothelial cells, thereby suggesting that oxLDL may be involved in cardiovascular diseases through neutrophil activation. As NETs comprise myeloperoxidase and proteases, they have the potential to mediate oxidative modification of LDL. This review summarizes recent updates on the analysis of NETs, their implications for cardiovascular diseases, and prospects for a possible link between NET formation and oxidative modification of lipoproteins.

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.

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