scholarly journals Chondroitin Sulfate N -acetylgalactosaminyltransferase-2 Impacts Foam Cell Formation and Atherosclerosis by Altering Macrophage Glycosaminoglycan Chain

2021 ◽  
Vol 41 (3) ◽  
pp. 1076-1091
Author(s):  
Imam Manggalya Adhikara ◽  
Keiko Yagi ◽  
Dyah Samti Mayasari ◽  
Yoko Suzuki ◽  
Koji Ikeda ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Scavenger Receptor ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Peritoneal Macrophages ◽  
Metabolic Phenotype ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell

Objective: Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfate N -acetylgalactosaminyltransferase-2), in macrophage foam cell formation. Approach and Results: ChGn-2-deficient mice showed decreased and shortened glycosaminoglycans. ChGn-2 −/− /LDLr −/− (low-density lipoprotein receptor) mice generated less atherosclerotic plaque after being fed with Western diet despite exhibiting a metabolic phenotype similar to that of the ChGn-2 +/+ /LDLr −/− littermates. We demonstrated that in macrophages, ChGn-2 expression was upregulated in the presence of oxLDL (oxidized LDL), and glycosaminoglycan was substantially increased. Foam cell formation was significantly altered by ChGn-2 in both mouse peritoneal macrophages and the RAW264.7 macrophage cell line. Mechanistically, ChGn-2 enhanced oxLDL binding on the cell surface, and as a consequence, CD36—an important macrophage membrane scavenger receptor—was differentially regulated. Conclusions: ChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.

scholarly journals Anti-Atherosclerotic Activity of (3R)-5-Hydroxymellein from an Endophytic Fungus Neofusicoccum parvum JS-0968 Derived from Vitex rotundifolia through the Inhibition of Lipoproteins Oxidation and Foam Cell Formation

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 715
Author(s):  
Jae-Yong Kim ◽  
Soonok Kim ◽  
Sang Hee Shim
Keyword(s):  
Conformational Changes ◽  
Endophytic Fungus ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Ldl Oxidation ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Neofusicoccum Parvum

An endophytic fungus, Neofusicoccum parvum JS-0968, was isolated from a plant, Vitex rotundifolia. The chemical investigation of its cultures led to the isolation of a secondary metabolite, (3R)-5-hydroxymellein. It has been reported to have antifungal, antibacterial, and antioxidant activity, but there have been no previous reports on the effects of (3R)-5-hydroxymellein on atherosclerosis. The oxidation of lipoproteins and foam cell formation have been known to be significant in the development of atherosclerosis. Therefore, we investigated the inhibitory effects of (3R)-5-hydroxymellein on atherosclerosis through low-density lipoprotein (LDL) and high-density lipoprotein (HDL) oxidation and macrophage foam cell formation. LDL and HDL oxidation were determined by measuring the production of conjugated dienes and malondialdehyde, the amount of hyperchromicity and carbonyl content, conformational changes, and anti-LDL oxidation. In addition, the inhibition of foam cell formation was measured by Oil red O staining. As a result, (3R)-5-hydroxymellein suppressed the oxidation of LDL and HDL through the inhibition of lipid peroxidation, the decrease of negative charges, the reduction of hyperchromicity and carbonyl contents, and the prevention of apolipoprotein A-I (ApoA-I) aggregation and apoB-100 fragmentation. Furthermore, (3R)-5-hydroxymellein significantly reduced foam cell formation induced by oxidized LDL (oxLDL). Taken together, our data show that (3R)-5-hydroxymellein could be a potential preventive agent for atherosclerosis via obvious anti-LDL and HDL oxidation and the inhibition of foam cell formation.

Abstract 333: CD36 Mediates Cholesterol Uptake via Na/K-ATPase/lyn Signaling in Macrophages

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Yiliang Chen ◽  
David Kennedy ◽  
Zhichuan Li ◽  
Zijian Xie ◽  
Roy L Silverstein
Keyword(s):  
Kinase Activity ◽  
Foam Cell ◽  
Oxidized Ldl ◽  
Scavenger Receptor ◽  
Cell Formation ◽  
Developed Countries ◽  
Foam Cell Formation ◽  
Macrophage Foam Cell ◽  
Cholesterol Uptake ◽  
Lyn Kinase

Atherosclerosis, the leading cause of death in the developed countries, is characterized by macrophage foam cell formation. We previously showed that CD36, a scavenger receptor highly expressed in macrophages, mediates oxidized-LDL uptake, contributes to intracellular cholesterol accumulation and foam cell formation, and regulates macrophage migration and pro-inflammatory signaling. Consistently, cd36 deletion in mice protects from diet-induced atherosclerosis. Mechanistically, we discovered a novel signaling pathway, in which oxidized LDL (oxLDL) binding to CD36 activates Lyn kinase and initiates a cascade that is necessary for the pro-atherogenic cellular phenotype. How CD36 regulates Lyn kinase remains undefined. Since we previously showed that the Na/K-ATPase (NKA) regulates Src family kinases, including Lyn, we hypothesized that CD36 regulates Lyn kinase via an interaction with NKA. We used co-immunoprecipitation, FRET, and a novel cross linking assay to demonstrate that CD36 physically associates with NKA on the macrophage surface. Using a Lyn kinase activity assay, we showed that the interaction regulates Lyn kinase activity in response to oxLDL in macrophages. Moreover, a newly developed peptide inhibitor specifically blocked Lyn activation in response to oxLDL and attenuated oxLDL-stimulated cholesterol uptake (135.6±3.4 μM cholesterol/mg protein after 24 hours vs 173.8±7.7 μM cholesterol/mg protein in vehicle treated cells; p=0.0005; n=6). Taken together, we conclude that CD36 signals through NKA to regulate Lyn kinase activity in macrophages, which may be a molecular mechanism underlying cholesterol overloading and foam cell formation.

Abstract 126: Chlamydia Pneumoniae Induces Foam Cell Formation Of Macrophages By Activating The TLR4/TRIF/IRF3 Pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Shuang Chen ◽  
Rosalinda Sorrentino ◽  
Kenichi Shimada ◽  
Timothy Crother ◽  
Moshe Arditi
Keyword(s):  
Transcriptional Control ◽  
Chlamydia Pneumoniae ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Peritoneal Macrophages ◽  
Foam Cell Formation ◽  
Toll Like Receptors ◽  
Macrophage Foam Cell

Background: Chlamydia pneumoniae (CP) induces macrophage foam cell formation (FCF), a key event in early atherosclerosis, in the presence of low-density lipoprotein (LDL). Recent studies have indicated the role of Toll-Like Receptors in atherogenesis. Liver X receptors (LXR) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism and determinants of atherosclerosis. Induction of LXR-activated genes has also been shown to influence the pathogen pattern recognition activity of the Toll-like receptors 3 and 4 (TLR3/4). The TLR and the LXR pathways converge on the transcription factor IRF3. Objective: We hypothesized that TLR and the LXR and IRF3 pathways participate in CP infection mediated FCF and acceleration of atherosclerosis, and that the MyD88- independent pathway via TLR4/TRIF and IRF3 play a role in this acceleration. Methods: Peritoneal macrophages were isolated from C57BL/6 wild type (WT) mice, IRF3 −/− mice, TLR4 −/− mice and TRIF −/− mice. Cells were treated with UV killed CP (UVCP, 5x10 5 IFU) with or without ox-LDL (100 μg/ml) in the presence or absence of LXR agonist GW3965 (2nM). LPS (10 ng/ml) and PolyI:C (1μg/ml) were used as positive controls as TLR4 and TLR3 ligands, respectively. FCF was examined by Oil Red O staining. The percentages of foam cells in total macrophages were quantified. Results : FCF was significantly reduced in IRF3−/− cells compared with WT cells stimulated with UVCP plus ox-LDL. Foam cells induced by LPS with ox-LDL were also significantly reduced in IRF3−/− cells compared to WT cells (p<0.05). Furthermore, the synthetic LXR agonist GW3965 significantly diminished CP induced FCF in WT cells. FCF was significantly reduced in TLR4−/− and TRIF−/− macrophages compared to WT cells when stimulated with UVCP with ox-LDL (p<0.05). Conclusion : Chlamydia pneumoniae infection can activate the TLR4/TRIF/IRF3 pathway and does play an important role in CP- mediated foam cell formation in macrophages. Therefore, infections such as the one caused by CP, can trigger the TLR4/TRIF/IRF3 pathway leading to the down regulation of LXRs and shifting of cholesterol transport toward pro-foam cell production and thereby accelerating atherogenesis.. Supported by NIH grants AI 067995 and HL66436 to MA.

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.

scholarly journals Combination Therapy with a Sodium-Glucose Cotransporter 2 Inhibitor and a Dipeptidyl Peptidase-4 Inhibitor Additively Suppresses Macrophage Foam Cell Formation and Atherosclerosis in Diabetic Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Michishige Terasaki ◽  
Munenori Hiromura ◽  
Yusaku Mori ◽  
Kyoko Kohashi ◽  
Hideki Kushima ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Foam Cell ◽  
Cell Formation ◽  
Peritoneal Macrophages ◽  
Foam Cell Formation ◽  
Diabetic Mice ◽  
Macrophage Foam Cell ◽  
Dipeptidyl Peptidase 4 ◽  
Sodium Glucose Cotransporter ◽  
Hba1c Levels

Dipeptidyl peptidase-4 inhibitors (DPP-4is), in addition to their antihyperglycemic roles, have antiatherosclerotic effects. We reported that sodium-glucose cotransporter 2 inhibitors (SGLT2is) suppress atherosclerosis in a glucose-dependent manner in diabetic mice. Here, we investigated the effects of combination therapy with SGLT2i and DPP-4i on atherosclerosis in diabetic mice. SGLT2i (ipragliflozin, 1.0 mg/kg/day) and DPP-4i (alogliptin, 8.0 mg/kg/day), either alone or in combination, were administered to db/db mice or streptozotocin-induced diabetic apolipoprotein E-null (Apoe−/−) mice. Ipragliflozin and alogliptin monotherapies improved glucose intolerance; however, combination therapy did not show further improvement. The foam cell formation of peritoneal macrophages was suppressed by both the ipragliflozin and alogliptin monotherapies and was further enhanced by combination therapy. Although foam cell formation was closely associated with HbA1c levels in all groups, DPP-4i alone or the combination group showed further suppression of foam cell formation compared with the control or SGLT2i group at corresponding HbA1c levels. Both ipragliflozin and alogliptin monotherapies decreased scavenger receptors and increased cholesterol efflux regulatory genes in peritoneal macrophages, and combination therapy showed additive changes. In diabetic Apoe−/− mice, combination therapy showed the greatest suppression of plaque volume in the aortic root. In conclusion, combination therapy with SGLT2i and DPP4i synergistically suppresses macrophage foam cell formation and atherosclerosis in diabetic mice.

Acrolein-conjugated low-density lipoprotein induces macrophage foam cell formation

2013 ◽  
Vol 227 (1) ◽  
pp. 51-57 ◽  
Author(s):  
Kenta Watanabe ◽  
Yuki Nakazato ◽  
Ryotaro Saiki ◽  
Kazuei Igarashi ◽  
Mitsukazu Kitada ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Low Density ◽  
Macrophage Foam Cell
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