scholarly journals Relationship of MMP-14 and TIMP-3 Expression with Macrophage Activation and Human Atherosclerotic Plaque Vulnerability

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Jason L. Johnson ◽  
Nicholas P. Jenkins ◽  
Wei-Chun Huang ◽  
Karina Di Gregoli ◽  
Graciela B. Sala-Newby ◽  
...  
Keyword(s):  
Foam Cell ◽  
Plaque Rupture ◽  
Oxidized Ldl ◽  
Foam Cells ◽  
Plaque Morphology ◽  
Atherosclerotic Plaques ◽  
Human Atherosclerosis ◽  
Anti Inflammatory ◽  
Relationship Of

Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective.MMP-14hi  TIMP-3lorabbit foam cells are more invasive and more prone to apoptosis thanMMP-14lo  TIMP-3hicells. We investigated the implications of these findings for human atherosclerosis.In vitrogenerated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction.

scholarly journals Role of adipokine zinc-α2-glycoprotein in coronary heart disease

2019 ◽  
Vol 317 (6) ◽  
pp. E1055-E1062
Author(s):  
Dandan Huang ◽  
Xiaoxiang Mao ◽  
Jiangtong Peng ◽  
Min Cheng ◽  
Tao Bai ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Foam Cell ◽  
Cell Formation ◽  
Foam Cell Formation ◽  
Atherosclerotic Plaques ◽  
293 Cells ◽  
Anti Inflammatory

Zinc-α2-glycoprotein (AZGP1) is a newly identified adipokine that is associated with lipid metabolism and vascular fibrosis. Although adipokines contribute to lipid dysfunction and its related diseases, including stroke and coronary heart disease (CHD), the role of AZGP1 remains unclear. In this study, the role of AZGP1 in atherosclerosis and CHD was investigated. Serum AZGP1 levels from control ( n = 84) and CHD ( n = 91) patients were examined by ELISA and its relationship with various clinical parameters was analyzed. Immunohistochemistry and immunofluorescence were used to detect the expression of AZGP1 and its receptor in coronary atherosclerotic arteries. THP-1 and human embryonic kidney 293 cells were used to verify its anti-inflammatory role in atherosclerosis. Serum AZGP1 levels in CHD patients were lower than controls ( P < 0.01) and independently associated with CHD prevalence ( P = 0.021). AZGP1 levels also inversely correlated with the Gensini score. Immunohistochemistry and immunofluorescence showed that AZGP1 and its receptor β3-adrenoceptor (β3-AR) colocalized in lipid-rich areas of atherosclerotic plaques, particularly around macrophages. In vitro, AZGP1 had no effect on foam cell formation but showed anti-inflammatory effects through its regulation of JNK/AP-1 signaling. In summary, AZGP1 is an anti-inflammatory agent that can be targeted for CHD treatment.

scholarly journals Anti-Inflammatory Effects of Dimethyl Fumarate in Microglia via an Autophagy Dependent Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Young-Sun Lee ◽  
Deepak Prasad Gupta ◽  
Sung Hee Park ◽  
Hyun-Jeong Yang ◽  
Gyun Jee Song
Keyword(s):  
Cytokine Production ◽  
Dimethyl Fumarate ◽  
Neuroprotective Effects ◽  
Autophagy Induction ◽  
The Central Nervous System ◽  
Anti Inflammatory ◽  
Lc3 Puncta ◽  
Relationship Of ◽  
Dependent Pathway

Dimethyl fumarate (DMF), which has been approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis, is considered to exert anti-inflammatory and antioxidant effects. Microglia maintain homeostasis in the central nervous system and play a key role in neuroinflammation, while autophagy controls numerous fundamental biological processes, including pathogen removal, cytokine production, and clearance of toxic aggregates. However, the role of DMF in autophagy induction and the relationship of this effect with its anti-inflammatory functions in microglia are not well known. In the present study, we investigated whether DMF inhibited neuroinflammation and induced autophagy in microglia. First, we confirmed the anti-neuroinflammatory effect of DMF in mice with streptozotocin-induced diabetic neuropathy. Next, we used in vitro models including microglial cell lines and primary microglial cells to examine the anti-inflammatory and neuroprotective effects of DMF. We found that DMF significantly inhibited nitric oxide and proinflammatory cytokine production in lipopolysaccharide-stimulated microglia and induced the switch of microglia to the M2 state. In addition, DMF treatment increased the expression levels of autophagy markers including microtubule-associated protein light chain 3 (LC3) and autophagy-related protein 7 (ATG7) and the formation of LC3 puncta in microglia. The anti-inflammatory effect of DMF in microglia was significantly reduced by pretreatment with autophagy inhibitors. These data suggest that DMF leads to the induction of autophagy in microglia and that its anti-inflammatory effects are partially mediated through an autophagy-dependent pathway.

Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation

2021 ◽  
Author(s):  
Jiao-Hui Wu ◽  
Lisheng Zhang ◽  
Igor Nepliouev ◽  
Leigh Brian ◽  
Taiqin Huang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Foam Cell ◽  
Atherosclerotic Lesion ◽  
Foam Cells ◽  
Actin Binding ◽  
Cross Sectional ◽  
Cell Transdifferentiation

Abstract Aims The F-actin-binding protein Drebrin inhibits smooth muscle cell (SMC) migration, proliferation and pro-inflammatory signaling. Therefore, we tested the hypothesis that Drebrin constrains atherosclerosis. Methods and results SM22-Cre+/Dbnflox/flox/Ldlr-/- (SMC-Dbn-/-/Ldlr-/-) and control mice (SM22-Cre+/Ldlr-/-, Dbnflox/flox/Ldlr-/-, and Ldlr-/-) were fed a Western diet for 14-20 weeks. Brachiocephalic arteries of SMC-Dbn-/-/Ldlr-/- mice exhibited 1.5- or 1.8-fold greater cross-sectional lesion area than control mice at 14 or 20 wk, respectively. Aortic atherosclerotic lesion surface area was 1.2-fold greater in SMC-Dbn-/-/Ldlr-/- mice. SMC-Dbn-/-/Ldlr-/- lesions comprised necrotic cores that were two-fold greater in size than those of control mice. Consistent with their bigger necrotic core size, lesions in SMC-Dbn-/- arteries also showed more transdifferentiation of SMCs to macrophage-like cells: 1.5- to 2.5-fold greater, assessed with BODIPY or with CD68, respectively. In vitro data were concordant: Dbn-/- SMCs had 1.7-fold higher levels of KLF4 and transdifferentiated to macrophage-like cells more readily than Dbnflox/flox SMCs upon cholesterol loading, as evidenced by greater up-regulation of CD68 and galectin-3. Adenovirally mediated Drebrin rescue produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs. During early atherogenesis, SMC-Dbn-/-/Ldlr-/- aortas demonstrated 1.6-fold higher levels of reactive oxygen species than control mouse aortas. The 1.8-fold higher levels of Nox1 in Dbn-/- SMCs was reduced to WT levels with KLF4 silencing. Inhibition of Nox1 chemically or with siRNA produced equivalent levels of macrophage-like transdifferentiation in Dbn-/- and Dbnflox/flox SMCs. Conclusions We conclude that SMC Drebrin limits atherosclerosis by constraining SMC Nox1 activity and SMC transdifferentiation to macrophage-like cells. Translational perspective Drebrin is abundantly expressed in vascular smooth muscle cells (SMCs) and is up-regulated in human atherosclerosis. A hallmark of atherosclerosis is the accumulation of foam cells that secrete pro-inflammatory cytokines and contribute to plaque instability. A large proportion of these foam cells in humans derive from SMCs. We found that SMC Drebrin limits atherosclerosis by reducing SMC transdifferentiation to macrophage-like foam cells in a manner dependent on Nox1 and KLF4. For this reason, strategies aimed at augmenting SMC Drebrin expression in atherosclerotic plaques may limit atherosclerosis progression and enhance plaque stability by bridling SMC-to-foam-cell transdifferentiation.

scholarly journals Cholesterol Acceptors Regulate the Lipidome of Macrophage Foam Cells

2019 ◽  
Vol 20 (15) ◽  
pp. 3784 ◽  
Author(s):  
Antoni Paul ◽  
Todd A. Lydic ◽  
Ryan Hogan ◽  
Young-Hwa Goo
Keyword(s):  
High Density Lipoprotein ◽  
Free Cholesterol ◽  
Foam Cell ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Atherosclerotic Plaques ◽  
Plaque Instability ◽  
Apolipoprotein A ◽  
Lipid Species ◽  
Macrophage Foam Cells

Arterial foam cells are central players of atherogenesis. Cholesterol acceptors, apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL), take up cholesterol and phospholipids effluxed from foam cells into the circulation. Due to the high abundance of cholesterol in foam cells, most previous studies focused on apoA-I/HDL-mediated free cholesterol (FC) transport. However, recent lipidomics of human atherosclerotic plaques also identified that oxidized sterols (oxysterols) and non-sterol lipid species accumulate as atherogenesis progresses. While it is known that these lipids regulate expression of pro-inflammatory genes linked to plaque instability, how cholesterol acceptors impact the foam cell lipidome, particularly oxysterols and non-sterol lipids, remains unexplored. Using lipidomics analyses, we found cholesterol acceptors remodel foam cell lipidomes. Lipid subclass analyses revealed various oxysterols, sphingomyelins, and ceramides, species uniquely enriched in human plaques were significantly reduced by cholesterol acceptors, especially by apoA-I. These results indicate that the function of lipid-poor apoA-I is not limited to the efflux of cholesterol and phospholipids but suggest that apoA-I serves as a major regulator of the foam cell lipidome and might play an important role in reducing multiple lipid species involved in the pathogenesis of atherosclerosis.

Geometrical and Morphological Assessment of Human Endarterectomy Specimens In Vitro

2013 ◽  
Author(s):  
Renate W. Boekhoven ◽  
Marcel C. M. Rutten ◽  
Marc R. H. M. van Sambeek ◽  
Frans N. van de Vosse ◽  
Richard G. P. Lopata
Keyword(s):  
Complex Geometry ◽  
Plaque Morphology ◽  
Atherosclerotic Plaques ◽  
Rupture Risk ◽  
Temporal And Spatial ◽  
Unstable Plaques ◽  
Stenotic Arteries ◽  
3D Information

Treatment of rupture-prone carotid atherosclerotic plaques, by means of endarterectomy, is only beneficial for patients with unstable plaques, which comprise only 16% of the patient population [1]. It is therefore of great interest to assess morphology, geometry and mechanical deformation of the plaque and its components, to prevent unnecessary treatment. However, due to the complex geometry of stenotic arteries, 3D information at both high temporal and spatial resolution is required. Besides, assessment of plaque morphology in vivo can still not be routinely performed. Therefore, one has to rely on in vitro methods to obtain morphology and mechanical properties, and thus rupture risk.

scholarly journals Quercetin Suppresses the Progression of Atherosclerosis by Regulating MST1-Mediated Autophagy in ox-LDL-Induced RAW264.7 Macrophage Foam Cells

2019 ◽  
Vol 20 (23) ◽  
pp. 6093 ◽  
Author(s):  
Hui Cao ◽  
Qingling Jia ◽  
Li Yan ◽  
Chuan Chen ◽  
Sanli Xing ◽  
...  
Keyword(s):  
Lipid Accumulation ◽  
Foam Cell ◽  
Cell Model ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Raw264.7 Macrophages ◽  
Age Related ◽  
Raw264.7 Macrophage ◽  
Senescence Phenotype

Objective: To investigate the process by which quercetin suppresses atherosclerosis by upregulating MST1-mediated autophagy in RAW264.7 macrophages. Methods: An in vitro foam cell model was established by culturing RAW264.7 macrophages with oxidized low-density lipoprotein (ox-LDL). The cells were treated with quercetin alone or in combination with the autophagy inhibitor, 3-methyladenine, and autophagy agonist, rapamycin. Cell viability was detected with a CCK-8 kit. Lipid accumulation was detected by oil red O staining, senescence was detected by SA-β-gal (senescence-associated β-galactosidase) staining, reactive oxygen species were detected by ROS assay kit. Autophagosomes and mitochondria were detected by transmission electron microscope (TEM), and expression of MST1, LC3-II/I, Beclin1, Bcl-2, P21, and P16 were detected by immunofluorescence and Western blot. Results: Ox-LDL induced RAW264.7 macrophage-derived foam cell formation, reduced survival, aggravated cell lipid accumulation, and induced a senescence phenotype. This was accompanied by decreased formation of autophagosome; increased expression of P53, P21, and P16; and decreased expression of LC3-II/I and Beclin1. After intervention with quercetin, the cell survival rate was increased, and lipid accumulation and senescence phenotype were reduced. Furthermore, the expression of LC3-II/I and Beclin1 were increased, which was consistent with the ability of quercetin to promote autophagy. Ox-LDL also increased the expression of MST1, and this increase was blocked by quercetin, which provided a potential mechanism by which quercetin may protect foam cells against age-related detrimental effects. Conclusion: Quercetin can inhibit the formation of foam cells induced by ox-LDL and delay senescence. The mechanism may be related to the regulation of MST1-mediated autophagy of RAW264.7 cells.

scholarly journals The capability of minor quaternary benzophenanthridine alkaloids to inhibit TNF-α secretion and cyclooxygenase activity

2017 ◽  
Vol 86 (3) ◽  
pp. 223-230 ◽  
Author(s):  
Jan Hošek ◽  
Kristýna Šebrlová ◽  
Petra Kaucká ◽  
Ondřej Peš ◽  
Eva Táborská
Keyword(s):  
Biological Effects ◽  
Benzophenanthridine Alkaloids ◽  
Additional Information ◽  
Tnf Α ◽  
Wide Range ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Relationship Of ◽  
Sanguinarine And Chelerythrine

Quaternary benzophenanthridine alkaloids are known to have a wide range of biological effects, including antimicrobial, antifungal, anti-inflammatory, and antitumour activities. However, only sanguinarine and chelerythrine have been studied intensively. The aim of this study was to evaluate the anti-inflammatory potential of the five minor quaternary benzophenanthridine alkaloids sanguilutine, sanguirubine, chelirubine, chelilutine, and macarpine in vitro and to compare them with more thoroughly studied sanguinarine and chelerythrine. Before making cell-based assays, the cytotoxicity of the alkaloids was evaluated. The anti-inflammatory potential of the chosen alkaloids was evaluated as for their ability to modulate the lipopolysaccharide-induced secretion of tumour necrosis factor α (TNF-α) in the macrophage-like cell line THP-1. The cyclooxygenase (COX)-1 and COX-2 inhibitory activities were also measured. The results indicate that the presence of a methylenedioxy ring attached at carbon (C)7-C8 is important for reducing the secretion of TNF-α. Interestingly, this effect did not show a simple dependence on concentration. The selected alkaloids showed little or no anti-COX activity. The results obtained from the present experiments may provide additional information useful in understanding the structure-to-activity relationship of the quaternary benzophenanthridine alkaloids. The anti-inflammatory potential and the cytotoxic effect are driven by the presence of a methylenedioxy ring attached at C7-C8 and C2-C3, respectively.

Abstract 18838: Inhibition and Genetic Deficiency of Trem-1 Receptor Reduces Development of Experimental Atherosclerosis in Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jérémie Joffre ◽  
Stephane Potteaux ◽  
Amir Boufenzer ◽  
Xavier Loyer ◽  
Safa Mellak ◽  
...  
Keyword(s):  
Oxidized Ldl ◽  
Experimental Atherosclerosis ◽  
Lesion Size ◽  
Atherosclerotic Plaques ◽  
Chow Diet ◽  
Chimeric Mice ◽  
Marrow Graft ◽  
Aortic Sinus ◽  
Stable Plaque

Introduction: Innate immunity, particularly monocytes / macrophages and neutrophils, play a major role in the development and the complications of atherosclerosis. TREM-1 is a recently discovered receptor expressed by myeloid cells that amplifies the inflammatory response by increasing chemokines and pro inflammatory cytokines production. The aim of this study was to determine the role of TREM-1 in experimental atherosclerosis. Methods and results: TREM-1 is not present in healthy artery but is expressed (mRNA and protein) in human carotid atherosclerotic plaques, mainly by macrophages. 8 week-old Ldlr-/ - mice were lethally irradiated and transplanted with a bone marrow graft Trem-1 + / + or Trem-1-/ - and put on a fat diet (FD) during 14 weeks. Cholesterol levels were not different between the two groups. In Ldlr-/-/Trem-1-/ - chimeric mice, we observed a 60% reduction of the lesion size in the aortic sinus (120100 ± 139600 vs 479116 ± 70229 μm2, P = 0.006) and a 49% reduction on the thoracic aorta (9.5 ± 2.2 vs 4.8 ± 1.6% surface ratio, P = 0.02). In Ldlr-/-/Trem-1-/- chimeric mice, plaques showed a significant decrease in macrophage infiltration (MOMA +, P=0.029) and a reduction in necrotic core size (Masson’s trichrome, P=0.003). In vitro, splenocytes from Ldlr-/-Trem-1-/- stimulated by oxidized LDL produced less IL-12 (ELISA) than control chimeric splenocytes (126 ±104 vs 1185 ± 795 pg/ml, P = 0.001). We have developed a dodecapeptide (LR-12) wich inhibits TREM-1 binding to its endogenous ligand. Apoe-/- mice were treated by daily intraperitoneal injections of LR-12 (100μg) or scramble peptide during 4 weeks. We observed that LR-12 treatment reduced atherosclerosis development on a chow diet (-30%, P <0.05) and on a high fat diet (-42%, P = 0.005). Conclusion: TREM-1 is expressed in human and mouse atherosclerotic plaques. TREM-1 genetic invalidation and pharmacological inhibition reduce the development of atherosclerosis and induce a more stable plaque phenotype.

scholarly journals SCAVENGER RECEPTOR-MEDIATED TARGETING OF MACROPHAGE FOAM CELLS IN ATHEROSCLEROTIC PLAQUE USING OLIGONUCLEOTIDE-FUNCTIONALIZED NANOPARTICLES

Nano LIFE ◽  
2010 ◽  
Vol 01 (03n04) ◽  
pp. 207-214 ◽  
Author(s):  
GAURAV SHARMA ◽  
ZHI-GANG SHE ◽  
DAVID T. VALENTA ◽  
WILLIAM B. STALLCUP ◽  
JEFFREY W. SMITH
Keyword(s):  
Atherosclerotic Plaque ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Scavenger Receptor ◽  
Foam Cells ◽  
Scavenger Receptors ◽  
Atherosclerotic Lesions ◽  
Macrophage Foam Cells ◽  
Progression Of Disease

Macrophage foam cells are key components of atherosclerotic plaque and play an important role in the progression of atherosclerosis leading to plaque rupture and thrombosis. Foam cells are emerging as attractive targets for therapeutic intervention and imaging the progression of disease. Therefore, designing nanoparticles (NPs) targeted to macrophage foam cells in plaque is of considerable therapeutic significance. Here we report the construction of an oligonucleotide-functionalized NP system with high affinity for foam cells. Nanoparticles functionalized with a 23-mer poly-Guanine (polyG) oligonucleotide are specifically recognized by the scavenger receptors on lipid-laden foam cells in vitro and ex vivo. The enhanced uptake of polyG-functionalized NPs by foam cells is inhibited in the presence of acetylated-LDL, a known ligand of scavenger receptors. Since polyG oligonucleotides are stable in serum and are unlikely to induce an immune response, they are a promising candidate for developing an NP platform for scavenger receptor-mediated targeting of macrophages that can be optimized for targeting foam cells in atherosclerotic lesions.

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