scholarly journals Increased Wnt5a mRNA Expression in Advanced Atherosclerotic Lesions, and Oxidized LDL Treated Human Monocyte-Derived Macrophages

2012 ◽  
Vol 5 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Pooja M. Bhatt
Keyword(s):  
Mrna Expression ◽  
Oxidized Ldl ◽  
Human Monocyte ◽  
Atherosclerotic Lesions

Abstract 512: The Long Non-coding Rna MIAT Regulates Smooth Muscle Cell Proliferation and Macrophage Activity in Advanced Atherosclerotic Lesions

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Yuhuang Li ◽  
Hong Jin ◽  
Ljubica Perisic ◽  
Ekaterina Chernogubova ◽  
Alexandra Bäcklund ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Oxidized Ldl ◽  
In Silico Analysis ◽  
Human Monocyte ◽  
Carotid Plaques ◽  
Knock Down ◽  
Plaque Stability ◽  
Atherosclerotic Lesions ◽  
Markers Of Inflammation

Background: Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators in various biological processes and diseases. Here we sought to identify and functionally characterize the lncRNA MIAT as a novel regulator in atherosclerotic plaque stability. Methods and results: We profiled RNA transcript expression in patients with advanced atherosclerotic lesions from the Biobank of Karolinska Endarterectomies (BiKE). By microarray analysis, lncRNA MIAT was identified as one of the most highly up-regulated non-coding RNAs in carotid plaques compared to iliac artery controls, which was confirmed by qRT-PCR and in situ hybridization. Additional in silico analysis indicated a substantial positive correlation of MIAT with markers of inflammation, apoptosis and matrix degradation in carotid plaques. Experimental knock-down of MIAT, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) not only markedly decreased proliferation and migration rates of cultured human carotid artery smooth muscle cells (hCASMCs), but also increased their levels of apoptosis. In addition, MIAT inhibition significantly impaired oxidized LDL (oxLDL) uptake of murine peritoneal as well as human monocyte-differentiated macrophages in vitro. In contrast, induction of MIAT expression by lipoprotein-a (LPa) treatment, displayed the opposite effect. Conditioned medium from macrophage cultures after MIAT knock-down substantially decreased hCASMC proliferation, indicating a potential involvement of MIAT in macrophage-SMC interactions during advanced stages of atherosclerosis. Conclusion: The lncRNA MIAT is a novel regulator of cellular processes in atherosclerosis and plaque stability, which influences SMC proliferation and apoptosis and interacts with disease-triggering macrophages.

Human tribbles homologue 2 is expressed in unstable regions of carotid plaques and regulates macrophage IL-10 in vitro

2009 ◽  
Vol 116 (3) ◽  
pp. 241-248 ◽  
Author(s):  
Jingti Deng ◽  
Christian H. James ◽  
Lisa Patel ◽  
Alberto Smith ◽  
Kevin G. Burnand ◽  
...  
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Human Monocyte ◽  
Interleukin 10 ◽  
Plaque Instability ◽  
Signalling Molecules ◽  
Atherosclerotic Lesions ◽  
Protein Kinase Signalling

Mammalian orthologues of the Drosophila tribbles protein (Trb1, Trb2 and Trb3) are a recently described family of signalling molecules that regulate gene expression by modulation of protein kinase signalling pathways. In the present study, a screen for mRNA species specifically regulated in vulnerable regions of human atherosclerotic plaque demonstrated the up-regulation of both Trb1 and Trb2, the latter by more than 8-fold. In vitro experiments in primary human monocyte-derived macrophages showed that Trb2 expression was up-regulated by treatment with oxidized LDL (low-density lipoprotein), and that expression of recombinant Trb2 specifically reduced macrophage levels of IL-10 (interleukin-10) mRNA. Our results thus identify Trb2 as a highly regulated gene in vulnerable atherosclerotic lesions, and demonstrate inhibition of macrophage IL-10 biosynthesis as a potential pro-inflammatory consequence of high Trb2 expression, which may contribute to plaque instability.

scholarly journals Oxidized LDL Increases and Interferon-γ Decreases Expression of CD36 in Human Monocyte–Derived Macrophages

1998 ◽  
Vol 18 (8) ◽  
pp. 1350-1357 ◽  
Author(s):  
Tsutomu Nakagawa ◽  
Shuichi Nozaki ◽  
Makoto Nishida ◽  
Janabi Mohamed Yakub ◽  
Yoshiaki Tomiyama ◽  
...  
Keyword(s):  
Oxidized Ldl ◽  
Human Monocyte ◽  
Interferon Γ

Abstract 276: SR-BI Suppresses Apoptosis by Reducing Endoplasmic Reticulum Stress and Promoting Akt Activity in Macrophages

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Huan Tao ◽  
Patricia G Yancey ◽  
Sean S Davies ◽  
L Jackson Roberts ◽  
John L Blakemore ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Apolipoprotein E ◽  
Er Stress ◽  
Cell Apoptosis ◽  
Free Cholesterol ◽  
Oxidized Ldl ◽  
Tunel Staining ◽  
Type I ◽  
Apoptotic Cells ◽  
Atherosclerotic Lesions

Objective: Macrophage apoptosis contributes to atherosclerotic plaque necrosis, inflammation, development and rupture. Scavenger receptor class B type I (SR-BI) is a key regulator of HDL metabolism and cellular cholesterol homeostasis. Here we examined the hypothesis that macrophage SR-BI modulates lipid-associated cellular stress and apoptosis. Methods and Results: In vitro cell apoptosis assays were performed in primary macrophages, and for in vivo evidence, we examined TUNEL staining of atherosclerotic lesions of LDLR -/- mice that were reconstituted with SR-BI -/- or WT bone marrow after 16 weeks on a Western diet. We found that SR-BI deficiency led to ~64.3% more apoptotic cells induced by oxidized LDL or free cholesterol in primary macrophages, and 6-fold more lesional apoptotic cells in SR-BI -/- →LDLR -/- mice compared to WT recipient mice. In macrophages, SR-BI deficiency caused significant accumulations of cellular free cholesterol and elevated markers of endoplasmic reticulum (ER) stress. These were exacerbated by feeding mice a high-cholesterol diet or inactivating the apolipoprotein E gene. Peroxidation of lipoproteins and cell membranes leads to modification of phosphatidylethanolamine by lipid aldehydes including isolevuglandins (IsoLG-PE). Treatment of macrophages with IsoLG-PE induced 52.6% more apoptotic cells in SR-BI -/- macrophages compared to WT. Transgenic expression of SR-BI by transfection of SR-BI -/- macrophages rescued oxidative stress-induced ER stress and cell apoptosis. SR-BI deficiency inhibited the Akt pathway compromising macrophage survival and increasing lesion necrosis. Moreover, Akt Activator was able to rescue SR-BI deficiency associated apoptosis in macrophages. Apolipoprotein E interacts with SR-BI in macrophages, co-operating for cellular lipid homeostasis and cell survival signaling. Conclusion: SR-BI protects against cell apoptosis induced by lipid stress in macrophages and atherosclerotic lesions. The underlying mechanisms are, at least in part, through reducing lipid-associated ER stress and promoting Akt activity in macrophages. Thus, we identify macrophage SR-BI-mediated apoptosis pathways as molecular targets for the prevention of atherosclerotic cardiovascular events.

Abstract 136: Identification of Melanoregulin as Novel Marker for Atherosclerosis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Silvia Aldi ◽  
Ljubica Perisic ◽  
Mariette Lengquist ◽  
Malin Kronqvist ◽  
Joy Roy ◽  
...  
Keyword(s):  
Carotid Plaque ◽  
Vascular Diseases ◽  
Human Monocyte ◽  
Foam Cells ◽  
Aortic Tissue ◽  
Atherosclerosis Progression ◽  
Protein Levels ◽  
Atherosclerotic Lesions ◽  
Novel Biomarkers ◽  
Human Carotid

Introduction: Novel biomarkers identification in atherosclerosis is needed for early detection/intervention of vascular diseases. Impaired lysosomal function and autophagy cause abnormal lipid accumulation in foam cells and contribute to atherosclerosis progression. By microarray of human carotid plaques in the Biobank of Karolinska Endarterectomies (BiKE), we found that melanoregulin (MREG), a protein associated with lysosomes, phagocytosis and autophagy and previously not associated with atherosclerosis, was significantly up-regulated in symptomatic (S) versus asymptomatic (AS) patients. MREG expression was also significantly correlated to inflammatory, lipid and endo/lysosome markers. Hypothesis: We hypothesized that MREG modulates clearance of engulfed lipids and extracellular material in lipid-loaded foam cells. Methods: MREG mRNA and protein levels were evaluated in human carotid plaque tissue from S and AS patients by qPCR and immunohistochemistry, respectively. MREG, together with lysosome and lipid markers (LAMP2 and PLIN2 respectively) was identified by immunofluorescence in human monocyte cells (THP-1), loaded with modified LDL. To investigate autophagy/MREG correlation, THP-1 cells were incubated with autophagy inhibitor (chloroquine, CQ) and MREG mRNA was assessed by qPCR. Results: MREG mRNA is elevated in human atherosclerotic lesions versus normal artery (11.21 folds, P<0.0001). In human aortic tissue MREG expression is correlated to the lesion progression and localizes in infiltrating macrophage-derived foam cells. In the human carotid plaque, MREG co-localizes with CD68+ and PLIN2+ cells, lined to the necrotic core. MREG protein was also detected in PMA-differentiated THP-1 cells. In lipid-loaded THP-1, MREG is co-localized with lysosomal LAMP2. Moreover, MREG expression is increased in THP-1 cells by incubation with PMA, starving medium and CQ. Conclusions: We show here for the first time that MREG is expressed in atherosclerotic lesions and is associated with endo/lysosomes in human macrophages. Furthermore we show that autophagy inhibition increases MREG mRNA expression. Future studies will investigate how MREG expression levels will affect phagocytic activity of lipid-loaded macrophages.

scholarly journals Treatment of macrophages with oxidized low-density lipoprotein increases their intracellular glutathione content

1991 ◽  
Vol 278 (2) ◽  
pp. 429-434 ◽  
Author(s):  
V M Darley-Usmar ◽  
A Severn ◽  
V J O'Leary ◽  
M Rogers
Keyword(s):  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Human Monocyte ◽  
Cell Types ◽  
Oxidative Modification ◽  
Glutathione Depletion ◽  
Lipid Phase ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein

Macrophages derived from the human monocyte cell line THP-1 or isolated from the peritoneum of C3H/HEJ mice were incubated with oxidized low-density lipoprotein (LDL) and the total glutathione content (oxidized plus reduced) was measured. An initial depletion of glutathione was followed by an increase, such that after a period of 24 h the glutathione content has approximately doubled. This response required the oxidation of the lipid phase of the LDL molecule, since both native LDL and acetylated LDL had little effect on glutathione levels. The response of the cells to oxidized LDL was dependent on the extent of oxidative modification of the protein. It was also found that 4-hydroxynonenal had a similar effect on THP-1 cells, and we suggest that this or other aldehydes present in oxidized LDL causes the induction of glutathione synthesis in response to an initial oxidative stress and consequent glutathione depletion. In addition, we found that both cell types possess transferases and peroxidases capable of detoxifying aldehydes and peroxides. However, treatment of cells with oxidized LDL or 4-hydroxynonenal for a period of 24 h had no effect on the activities of these enzymes.

scholarly journals Activation of Human Dendritic Cells Is Modulated by Components of the Outer Membranes of Neisseria meningitidis

2003 ◽  
Vol 71 (10) ◽  
pp. 5590-5597 ◽  
Author(s):  
Tamara Al-Bader ◽  
Myron Christodoulides ◽  
John E. Heckels ◽  
Judith Holloway ◽  
Amanda E. Semper ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Neisseria Meningitidis ◽  
Mrna Expression ◽  
Mhc Class Ii ◽  
Human Monocyte ◽  
Class Ii ◽  
Effective Vaccine ◽  
Tlr4 Mrna ◽  
Mhc Class Ii Molecules

ABSTRACT Neisseria meningitidis serogroup B is a major cause of life-threatening meningitis and septicemia worldwide, and no effective vaccine is available. Initiation of innate and acquired immune responses to N. meningitidis is likely to be dependent on cellular responses of dendritic cells (DC) to antigens present in the outer membrane (OM) of the meningococcus. In this study, the responses of human monocyte-derived DC (mo-DC) to OM isolated from parent (lipopolysaccharide [LPS]-replete) meningococci and from a mutant deficient in LPS were investigated. Parent OM selectively up-regulated Toll-like receptor 4 (TLR4) mRNA expression and induced mo-DC maturation, as reflected by increased production of chemokines, proinflammatory cytokines, and CD83, CD80, CD86, CD40, and major histocompatibility complex (MHC) class II molecules. In contrast, LPS-deficient OM selectively up-regulated TLR2 mRNA expression and induced moderate increases in both cytokine production and expression of CD86 and MHC class II molecules. Preexposure to OM, with or without LPS, augmented the allostimulatory properties of mo-DC, which induced proliferation of naive CD4+ CD45RA+ T cells. In addition, LPS-replete OM induced a greater gamma interferon/interleukin-13 ratio in naive T cells, whereas LPS-deficient OM induced the reverse profile. These data demonstrate that components of the OM, other than LPS, are also likely to be involved in determining the levels of DC activation and the nature of the T-helper immune response.

scholarly journals Oncostatin M promotes biphasic tissue factor expression in smooth muscle cells: evidence for Erk-1/2 activation

Blood ◽  
2001 ◽  
Vol 97 (3) ◽  
pp. 692-699 ◽  
Author(s):  
Toshiya Nishibe ◽  
Graham Parry ◽  
Atsushi Ishida ◽  
Salim Aziz ◽  
Jacqueline Murray ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Dna Binding ◽  
Smooth Muscle Cells ◽  
Mrna Expression ◽  
Tissue Factor ◽  
Muscle Cells ◽  
Binding Activity ◽  
Oncostatin M ◽  
Dna Binding Activity ◽  
Atherosclerotic Lesions

Abstract Tissue factor (TF), a transmembrane glycoprotein, initiates the extrinsic coagulation cascade. TF is known to play a major role in mediating thrombosis and thrombotic episodes associated with the progression of atherosclerosis. Macrophages at inflammatory sites, such as atherosclerotic lesions, release numerous cytokines that are capable of modulating TF expression. This study examined the role of oncostatin M (OSM), a macrophage/ T-lymphocyte–restricted cytokine, in the expression of TF in vascular smooth muscle cells (SMCs). It is reported here that OSM stimulated a biphasic and sustained pattern of TF messenger RNA (mRNA). The effect of OSM on TF mRNA expression was regulated at the transcriptional level as determined by nuclear run-offs and transient transfection of a TF promoter-reporter gene construct. OSM-induced TF expression was regulated primarily by the transcription factor NF-κB. Activation of NF-κB by OSM did not require IκB-α degradation. Inhibition of MEK activity by U0126 prevented OSM-induced TF expression by suppressing NF-κB DNA binding activity as determined by gel-shift analysis. Further, inhibition of Erk-1/2 protein by antisense treatment resulted in suppression of TF mRNA expression, indicating a role for Erk-1/2 in modulating NF-κB DNA binding activity. These studies suggest that the induced expression of TF by OSM is primarily through the activation of NF-κB and that activation of NF-κB is regulated in part by the MEK/Erk-1/2 signal transduction pathway. This study indicates that OSM may play a key role in promoting TF expression in SMCs within atherosclerotic lesions.

99 Effects of Combined TLR Stimulation on Interleukin-27 mRNA Expression in Human Monocyte-derived Dendritic Cells

Cytokine ◽  
2007 ◽  
Vol 39 (1) ◽  
pp. 27
Author(s):  
Claudius U. Meyer ◽  
Doreen Krumbiegel ◽  
Helena Markus ◽  
Michaela Fuidl ◽  
Fred Zepp
Keyword(s):  
Dendritic Cells ◽  
Mrna Expression ◽  
Human Monocyte ◽  
Interleukin 27
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