Abstract 1131: PARP1 is required for Adhesion Molecule Expression in Atherogenesis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Tobias Lukowicz von ◽  
Paul O Hassa ◽  
Christine Lohmann ◽  
Jan Borén ◽  
Vincent Braunersreuther ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Endothelial Activation ◽  
Chronic Inflammatory Disease ◽  
Parp Inhibition ◽  
High Cholesterol Diet ◽  
Fibrous Cap ◽  
Parp Activity

Objective - Atherosclerosis is a chronic inflammatory disease resulting from the interaction between modified lipoproteins, activated endothelial cells, macrophages, T-cells, and elements of the arterial wall. However, the key mediators linking recruitment of inflammatory cells to atherogenesis remain poorly defined. Poly(ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme that plays a role in acute inflammatory responses of cells and organs. Methods and Results - After 12 weeks of high-cholesterol diet, plaque formation in male apolipoprotein E- deficient mice was decreased by chronic inhibition of enzymatic PARP activity or genetic deletion of PARP1 by 46 or 51 %, respectively ( P < 0.05, n ≥ 9). Pharmacological PARP inhibition using PJ34 or PARP 1 deletion reduced PARP activity and diminished expression of inducible nitric oxide synthase (iNOS), vascular cell adhesion molecule-1 (VCAM-1), P-, and E-selectin (see Figure ). Furthermore, chronic PARP inhibition reduced plaque macrophage (CD68) and T-cell infiltration (CD3), increased fibrous cap thickness, and decreased necrotic core size and cell death ( P < 0.05, n ≥ 6). Conclusions - Our data provide pharmacologic and genetic evidence that endogenous PARP1 is required for the development of atherosclerosis in vivo by increasing adhesion molecules due to endothelial activation, enhancing inflammation, and inducing features of plaque vulnerability. Thus, inhibition of PARP1 may represent a promising novel therapeutic target in atherosclerosis.

Silencing of junctional adhesion molecule-like protein attenuates atherogenesis and enhances plaque stability in ApoE−/− mice

2019 ◽  
Vol 133 (11) ◽  
pp. 1215-1228 ◽  
Author(s):  
Yu Sun ◽  
Juan Guan ◽  
Yunfeng Hou ◽  
Fei Xue ◽  
Wei Huang ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Wound Repair ◽  
Inflammatory Responses ◽  
Atherosclerotic Lesion ◽  
Atherosclerotic Plaques ◽  
Plaque Stability ◽  
Fibrous Cap ◽  
Enhanced Expression

Abstract Background: Although junctional adhesion molecule-like protein (JAML) has recently been implicated in leukocyte recruitment during inflammation and wound repair, its role in atherosclerosis remains to be elucidated. Methods and results: First, we showed that JAML was strongly expressed in atherosclerotic plaques of cardiovascular patients. Similar results were obtained with atherosclerotic plaques of ApoE−/− mice. Co-immunofluorescence staining showed that JAML was mainly expressed in macrophages. Enhanced expression of JAML in cultured macrophages was observed following exposure of the cells to oxLDL. The functional role of JAML in atherosclerosis and macrophages function was assessed by interference of JAML with shRNA in vivo and siRNA in vitro. Silencing of JAML in mice significantly attenuated atherosclerotic lesion formation, reduced necrotic core area, increased plaque fibrous cap thickness, decreased macrophages content and inflammation. In addition, histological staining showed that JAML deficiency promoted plaques to stable phenotype. In vitro, JAML siRNA treatment lowered the expression of inflammatory cytokines in macrophages treated with oxLDL. The mechanism by which JAML mediated the inflammatory responses may be related to the ERK/NF-κB activation. Conclusions: Our results demonstrated that therapeutic drugs which antagonize the function of JAML may be a potentially effective approach to attenuate atherogenesis and enhance plaque stability.

scholarly journals The Anti-Inflammatory Effects of Angiogenin in an Endotoxin Induced Uveitis in Rats

2020 ◽  
Vol 21 (2) ◽  
pp. 413
Author(s):  
Jihae Park ◽  
Jee Taek Kim ◽  
Soo Jin Lee ◽  
Jae Chan Kim
Keyword(s):  
Western Blot ◽  
Inflammatory Cytokines ◽  
Aqueous Humor ◽  
Rat Model ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Ocular Tissue ◽  
Tnf Α ◽  
Anti Inflammatory

Angiogenin (ANG) is involved in the innate immune system and inflammatory disease. The aim of this study is to evaluate the anti-inflammatory effects of ANG in an endotoxin induced uveitis (EIU) rat model and the pathways involved. EIU rats were treated with balanced salt solution (BSS), a non-functional mutant ANG (mANG), or wild-type ANG (ANG). The integrity of the blood-aqueous barrier was evaluated by the infiltrating cell and protein concentrations in aqueous humor. Histopathology, Western blot, and real-time qRT-PCR of aqueous humor and ocular tissue were performed to analyze inflammatory cytokines and transcription factors. EIU treated with ANG had decreased inflammatory cells and protein concentrations in the anterior chamber. Compared to BSS and mANG, ANG treatment showed reduced expression of IL-1β, IL-8, TNF-α, and Myd88, while the expression of IL-4 and IL-10 was increased. Western blot of ANG treatment showed decreased expression of IL-6, inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and phosphorylated NF-κB and increased expression of IL-10. In conclusion, ANG seems to reduce effectively immune mediated inflammation in the EIU rat model by reducing the expression of proinflammatory cytokines, while increasing the expression of anti-inflammatory cytokines through pathways related to NF-κB. Therefore, ANG shows potential for effectively suppressing immune-inflammatory responses in vivo.

TRAF-1 Deficient Mice Show Impaired Monocyte Recruitment and Decreased Atherogenesis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 696-696
Author(s):  
Anna Missiou ◽  
Natascha Köstlin ◽  
Christian Münkel ◽  
Dietmar Pfeifer ◽  
Katja Zirlik ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Chemokine Receptors ◽  
Inflammatory Diseases ◽  
Inflammatory Cells ◽  
Adaptor Proteins ◽  
High Cholesterol Diet ◽  
Cell Content ◽  
Monocyte Recruitment

Abstract Members of the tumor necrosis factor (TNF) interleukin/toll-like receptor superfamily such as CD40L, TNFa, and IL-1b potently promote atherogenesis in mice and likely also in humans. TNF receptor associated factors (TRAFs) are cytoplasmic adaptor proteins for this group of cytokines. We recently reported over-expression of TRAFs in murine and human atheromata and demonstrated dependency of classic inflammatory functions on TRAFs in endothelial cells and macrophages. Here we test the hypothesis that TRAF-1 modulates atherogenesis in vivo. TRAF-1--/LDLR--mice fed a high cholesterol diet for 18 weeks developed significantly smaller atherosclerotic lesions compared with LDLR--controls. Intimal lesion size decreased by up to 56±6% and 33±5% in sections of the aortic arch and aortic root, respectively (n>10 per group, P<0.01 each). Plaques of TRAF-1-deficient animals contained up to 46±9% and 55±4% fewer macrophages while smooth muscle cell content increased by up to 32±6 and 36±7%, characteristics associated with non disrupted plaques in humans. Lipid content, collagen content, and lymphocyte content remained unchanged. In vitro, gene expression profiling revealed reduced expression of adhesion molecules (VCAM-1, ICAM-1), chemokines (CCL2, CXCL2), and growth factors (M-CSF) in TRAF-1-deficient endothelial cells as well as of integrins (CD29, CD11b) and chemokines/chemokine receptors (CXCL2, CCR1) in TRAF-1-deficient macrophages, verified by siRNA studies in human cells. Finally, both deficiency of TRAF-1 in endothelial cells and neutrophils/monocytes reduced adhesion of inflammatory cells to the endothelium in static and dynamic adhesion assays. We present the novel finding that TRAF 1 deficiency attenuates atherogenesis in mice, an effect most likely mediated by impaired monocyte recruitment to the vessel wall. These data identify TRAF-1 as potential treatment target for chronic inflammatory diseases such as atherosclerosis.

scholarly journals Ischemia-reperfusion induced microvascular responses in LDL-receptor −/− mice

1999 ◽  
Vol 276 (5) ◽  
pp. H1647-H1654 ◽  
Author(s):  
Naoharu Mori ◽  
Yoshinori Horie ◽  
Mary E. Gerritsen ◽  
D. Neil Granger
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Normal Diet ◽  
Intercellular Adhesion Molecule ◽  
High Cholesterol Diet ◽  
Wild Type ◽  
Intercellular Adhesion Molecule 1 ◽  
Rolling Velocity ◽  
Albumin Leakage

The objective of this study was to determine whether the microvascular responses to ischemia and reperfusion (I/R) are altered in an animal model of atherosclerosis, the low-density lipoprotein-receptor knockout (LDLr −/−) mouse. Intravital video microscopy was used to monitor venular wall shear rate, leukocytes rolling velocity, the number of rolling, adherent and emigrated leukocytes, and albumin leakage in cremasteric postcapillary venules of wild-type (B6129) and LDLr −/− mice exposed to 60 min of ischemia and 60 min of reperfusion. The postcapillary venules of LDLr −/− mice exhibited two- to threefold larger increments in the number of adherent leukocytes and a more profound albumin leakage response to I/R than venules in wild-type mice. The exaggerated inflammatory responses noted in LDLr −/− mice placed on a normal diet were not exacerbated by a high-cholesterol diet. Treatment of LDLr −/− mice with either a platelet-activating factor (PAF) receptor antagonist (WEB-2086) or a monoclonal antibody (YN-1) against the endothelial cell adhesion molecule, intercellular adhesion molecule 1 (ICAM-1), markedly attenuated the I/R-induced leukocyte adherence and albumin leakage. These findings indicate that atherogenic mice are more vulnerable to the deleterious microvascular effects of I/R and that PAF-mediated, ICAM-1-dependent leukocyte adhesion contributes to this exaggerated response to I/R.

scholarly journals Modulation of Immune Complex–induced Inflammation In Vivo by the Coordinate Expression of Activation and Inhibitory Fc Receptors

1999 ◽  
Vol 189 (1) ◽  
pp. 179-186 ◽  
Author(s):  
Raphael Clynes ◽  
Jay S. Maizes ◽  
Rodolphe Guinamard ◽  
Masao Ono ◽  
Toshiyuki Takai ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Immune Complexes ◽  
Inflammatory Responses ◽  
Fc Receptors ◽  
Inflammatory Cells ◽  
Neutrophil Infiltration ◽  
Calcium Flux ◽  
Deficient Mice

Autoantibodies and immune complexes are major pathogenic factors in autoimmune injury, responsible for initiation of the inflammatory cascade and its resulting tissue damage. This activation results from the interaction of immunoglobulin (Ig)G Fc receptors containing an activation motif (ITAM) with immune complexes (ICs) and cytotoxic autoantibodies which initiates and propagates an inflammatory response. In vitro, this pathway can be interrupted by coligation to FcγRIIB, an IgG Fc receptor containing an inhibitory motif (ITIM). In this report, we describe the in vivo consequences of FcγRII deficiency in the inflammatory response using a mouse model of IC alveolitis. At subthreshold concentrations of ICs that fail to elicit inflammatory responses in wild-type mice, FcγRII-deficient mice developed robust inflammatory responses characterized by increased hemorrhage, edema, and neutrophil infiltration. Bronchoalveolar fluids from FcγRII−/− stimulated mice contain higher levels of tumor necrosis factor and chemotactic activity, suggesting that FcγRII deficiency lowers the threshold of IC stimulation of resident cells such as the alveolar macrophage. In contrast, complement- and complement receptor–deficient mice develop normal inflammatory responses to suprathreshold levels of ICs, while FcRγ−/− mice are completely protected from inflammatory injury. An inhibitory role for FcγRII on macrophages is demonstrated by analysis of FcγRII−/− macrophages which show greater phagocytic and calcium flux responses upon FcγRIII engagement. These data reveal contrasting roles for the cellular receptors for IgG on inflammatory cells, providing a regulatory mechanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM FcγR expression. Exploiting the FcγRII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.

scholarly journals Interleukin-17-Producing CD4+ T Cells Promote Inflammatory Response and Foster Disease Progression in Hyperlipidemic Patients and Atherosclerotic Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Yin Wang ◽  
Wenming Li ◽  
Tingrui Zhao ◽  
Yao Zou ◽  
Tao Deng ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Th17 Cells ◽  
Early Stage ◽  
Inflammatory Cells ◽  
Chronic Inflammatory Disease ◽  
Interleukin 17 ◽  
Atherosclerotic Lesions ◽  
High Level

Atherosclerosis is a chronic inflammatory disease. Interleukin-17-producing CD4+ T cells (Th17 cells) play important roles in the progression of atherosclerosis. However, most of the studies were focused on the advanced stage of atherosclerosis. In the current study, we investigated the roles of Th17 cells, relevant mechanisms in hyperlipidemic patients, and different stages of atherosclerotic mice. Human blood samples were collected, and percentages of Th17 cells, macrophages, and neutrophils were analyzed by flow cytometry. ApoE−/− mice were fed with high-fat diet (HFD) and sacrificed at different time points to evaluate the infiltration of inflammatory cells at different stages of atherosclerosis. Furthermore, essential mechanisms of IL-17A in atherosclerotic inflammatory milieu formation were studied in vivo by intraperitoneal injection with monoclonal anti-murine IL-17 antibody. Our study reveals the higher percentages of Th17 cells, monocytes, and neutrophils in hyperlipidemic patients compared to healthy donors. Meanwhile, we also identify an infiltration of Th17 cells in the early stage of atherosclerosis (4 weeks after HFD), which maintains at high level until late stage of atherosclerosis (20 weeks after HFD). What is more, inflammatory cells including macrophages and neutrophils were also accumulated in atherosclerotic lesions. Neutralization of IL-17 in ApoE−/− mice resulted in less infiltration of macrophages and neutrophils and smaller atherosclerotic lesions. Importantly, in accordance with what is found in the mouse model, positive correlations between Th17 cells and macrophages or neutrophils were observed in hyperlipidemic patients. In conclusion, our clinical and mouse model data together reveal a pro-atherogenic role of Th17 cells through the promotion of inflammation in hyperlipidemic conditions and different stages of atherosclerosis, which further supports the notion that IL-17 may be a therapy target for the treatment of atherosclerosis.

scholarly journals Diflunisal targets the HMGB1/CXCL12 heterocomplex and blocks immune cell recruitment

2019 ◽  
Author(s):  
Federica De Leo ◽  
Giacomo Quilici ◽  
Mario Tirone ◽  
Valeria Mannella ◽  
Francesco De Marchis ◽  
...  
Keyword(s):  
Rational Design ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Cell Recruitment ◽  
Redox States ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

AbstractExtracellular HMGB1 triggers inflammation following infection or injury, and supports tumorigenesis in inflammation-related malignancies. HMGB1 has several redox states: reduced HMGB1 recruits inflammatory cells to injured tissues forming a heterocomplex with CXCL12 and signaling via its receptor CXCR4; disulfide-containing HMGB1 binds to TLR4 and promotes inflammatory responses. Here we show that Diflunisal, an aspirin-like nonsteroidal anti-inflammatory drug (NSAID) that has been in clinical use for decades, specifically inhibits in vitro and in vivo the chemotactic activity of HMGB1 at nanomolar concentrations, at least in part by binding directly to both HMGB1 and CXCL12 and disrupting their heterocomplex. Importantly, Diflunisal does not inhibit TLR4-dependent responses. Our findings clarify the mode of action of Diflunisal, and open the way to the rational design of functionally specific anti-inflammatory drugs.

scholarly journals miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses

2009 ◽  
Vol 106 (37) ◽  
pp. 15819-15824 ◽  
Author(s):  
Gang Liu ◽  
Arnaud Friggeri ◽  
Yanping Yang ◽  
Young-Jun Park ◽  
Yuko Tsuruta ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Negative Regulator ◽  
Microbial Pathogens ◽  
Cellular Activation ◽  
Mouse Macrophages ◽  
Non Coding Rnas ◽  
Maximal Induction

Toll-like receptors (TLRs) are major receptors that enable inflammatory cells to recognize invading microbial pathogens. MicroRNAs are small non-coding RNAs that play important regulatory roles in a variety of biological processes. In this study, we found that a microRNA, miR-147, was induced upon stimulation of multiple TLRs and functioned as a negative regulator of TLR-associated signaling events in murine macrophages. We first demonstrated that the NMES1 transcript was a functional primary miR-147. miR-147 was induced in LPS-stimulated mouse macrophages and under in vivo conditions in the lungs of LPS-treated mice. Expression of miR-147 was greater after cellular activation by TLR4 than after engagement of either TLR2 or TLR3, suggesting that maximal induction of miR-147 required activation of both NF-κB and IRF3. TLR4-induced miR-147 expression was both MyD88- and TRIF-dependent. The miR-147 promoter was responsive to TLR4 stimulation and both NF-κB and STAT1α bound to the miR-147 promoter. miR-147 mimics or induced expression of miR-147 decreased, whereas miR-147 knockdown increased inflammatory cytokine expression in macrophages stimulated with ligands to TLR2, TLR3, and TLR4. These data demonstrate a negative-feedback loop in which TLR stimulation induces miR-147 to prevent excessive inflammatory responses.

Neuropilin-VEGF signaling pathway acts as a key modulator of vascular, lymphatic, and inflammatory cell responses of the bladder to intravesical BCG treatment

2010 ◽  
Vol 299 (6) ◽  
pp. F1245-F1256 ◽  
Author(s):  
Marcia R. Saban ◽  
Thomas J. Sferra ◽  
Carole A. Davis ◽  
Cindy Simpson ◽  
Arielle Allen ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Inflammatory Responses ◽  
Lymphatic Vessels ◽  
Inflammatory Cells ◽  
Bladder Cancer Cell Line ◽  
Vegf Receptors ◽  
Human Bladder ◽  
Bladder Urothelium ◽  
Bladder Inflammation

Recent findings indicate that VEGF receptors and coreceptors (neuropilins; NRP) are expressed on nonendothelial cells in human bladder urothelium, in one human bladder cancer cell line (J82), and in the mouse bladder urothelium. In addition, VEGFR1, VEGFR2, NRP1, and NRP2 expressions were upregulated in animal models of chronic bladder inflammation induced by four weekly instillations of protease-activated receptors (PAR)-activating peptides or bacillus Calmette-Guérin (BCG) into the mouse bladder. Here, we used four weekly instillations of BCG as a model for chronic bladder inflammation to further investigate whether VEGF receptors and NRPs play a role in the migration of inflammatory cells and inflammation-induced lymphangiogenesis and angiogenesis. For this purpose, we used neutralizing antibodies that were engineered to specifically block the binding of VEGF to NRP (anti-NRP1B) and the binding of semaphorins to NRP (anti-NRP1A). C57BL/6 mice received intraperitoneal injections of PBS, anti-NRP1A- or anti-NRP1B-neutralizing antibodies and then were challenged chronically with intravesical PBS or BCG. At the end of chronic challenge period, a fluorescent internalizable tracer, scVEGF/Cy5.5, was administered to all mice and near-infrared fluorescence images were obtained in vivo and in real time. BCG increased the overall accumulation of scVEGF/Cy5.5 in the urinary bladder urothelium and inflammatory cells. In addition, BCG increased the density of blood and lymphatic vessels concomitantly with an upregulation of NRP2 expression in lymphatic vessels. Treatment of the mice with NRP1-neutralizing antibodies dramatically reduced scVEGF/Cy5.5 uptake, polymorphonuclear (myeloperoxidase-positive cells) and dendritic cell (CD11c-positive cells) infiltration, and decreased the overall density of BCG-induced blood and lymphatic vessels. These results implicate NRPs as critical in vivo regulators of the vascular and inflammatory responses to the intravesical administration of BCG.

The impact of selectins on mortality in stable carotid atherosclerosis

2015 ◽  
Vol 114 (09) ◽  
pp. 632-638 ◽  
Author(s):  
Matthias Hoke ◽  
Max-Paul Winter ◽  
Oswald Wagner ◽  
Markus Exner ◽  
Martin Schillinger ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Cardiovascular Mortality ◽  
Carotid Atherosclerosis ◽  
Leukocyte Adhesion ◽  
Inflammatory Cells ◽  
Endothelial Activation ◽  
Cellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
The Impact

SummaryCellular adhesion molecules also known as selectins promote recruitment of inflammatory cells into the arterial wall where they interact with lipid particles leading subsequently to plaque formation. The intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule-1 (VCAM-1) and the endothelial-leukocyte adhesion molecule 1 (ELAM-1) also known as E-selectin mediate the attachment of leukocytes and have been implicated in the destabilisation of atherosclerotic plaques. Therefore, we hypothesised that plasma selectin levels are associated with adverse clinical outcome. We prospectively studied 855 patients with sonographically confirmed carotid atherosclerosis. During a median follow-up of 6.2 years, corresponding to 5,551 overall person-years, 275 patients (26 %) died. We detected a significant association between cardiovascular mortality and ICAM-1 (adjusted hazard ratio [HR]: 3.43, 95 % confidence interval [CI] 2.00–5.88, p< 0.001) as well as VCAM-1 (adjusted HR: 2.51, 95 % CI 1.45–4.34, p=0.001) when comparing the fourth with the first quartile. Comparable results were obtained for all-cause mortality. In contrast, we could not detect a significant association between E-selectin and all-cause or cardiovascular mortality. We identified the selectins ICAM-1 and VCAM-1 as strong and independent predictors of all-cause and cardiovascular mortality in patients with stable carotid atherosclerosis. These molecules are elevated in states of endothelial activation and might assist to monitor anti-atherosclerotic therapy and select those patients with carotid atherosclerosis, who are at higher risk for cardiovascular events.

Sign in / Sign up

Export Citation Format

Share Document