Abstract 3373: MRP-8/14 is Critical for the Biological Response to Vascular Injury

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kevin Croce ◽  
Huiyun Gao ◽  
Yunmei Wang ◽  
Masashi Sakuma ◽  
Toshifumi Mooroka ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Cellular Proliferation ◽  
Cell Function ◽  
Transcriptional Profiling ◽  
Vascular Inflammation ◽  
Atherosclerotic Lesion ◽  
Biological Response ◽  
Myeloid Cell ◽  
Neutrophil Accumulation ◽  
Increased Risk

Background : MRP-8 (S100A8) and MRP-14 (S100A9) are members of the S100-family of calcium-modulated proteins that regulate myeloid cell function and control inflammation, in part, through activation of toll-like receptor-4 and RAGE. Using a transcriptional profiling approach in patients with acute coronary syndromes, we made the novel discovery that MRP-14 is associated with atherothrombosis, and demonstrated that elevated plasma levels of MRP-8/14 heterodimer predict increased risk of first and recurrent cardiovascular events. Despite functioning as a pro-inflammatory mediator, the role of MRP-8/14 in vascular inflammation and disease are unknown. Methods and Results : We evaluated vascular inflammation in wild-type (WT) and MRP-14-deficient (MRP-14 −/− ) mice that lack MRP-8/14 complexes with experimental arterial injury, vasculitis, or atherosclerosis. After femoral artery wire injury, MRP-14 −/− mice had a 33% reduction in leukocyte accumulation ( P =.0004) and a 72% reduction in cellular proliferation ( P =0.001) in the arterial wall followed by a 45% reduction in neointima formation ( P =0.004) compared to WT mice. In a cytokine-induced local Schwartzman-like reaction that produces thrombohemorrhagic vasculitis, MRP-14 −/− mice had a 59% reduction in lesion severity ( P <0.0001), an 82% smaller hemorrhagic area ( P =0.015), and a 45% decline in neutrophil accumulation ( P =0.013). Finally, in response to high-fat feeding, mice doubly deficient in ApoE and MRP-8/14 complexes had attenuation in atherosclerotic lesion area by 34% ( P =0.023) and a 60% decrease in macrophage accumulation in plaques ( P =0.021) compared to mice deficient in ApoE alone. Conclusions: This study demonstrates that MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury. Targeting MRP-8/14 may provide a novel therapeutic approach to modulate diverse forms of vascular injury, including restenosis, vasculitis, and atherosclerosis.

scholarly journals Mechanistic Links between Non-Coding RNAs and Myeloid Cell Inflammation in Atherosclerosis

2019 ◽  
Vol 119 (08) ◽  
pp. 1205-1211
Author(s):  
Valentina Paloschi ◽  
Hanna Winter ◽  
Joana Viola ◽  
Oliver Soehnlein ◽  
Lars Maegdefessel
Keyword(s):  
Messenger Rna ◽  
Vascular Inflammation ◽  
Myeloid Cells ◽  
Atherosclerotic Lesion ◽  
Myeloid Cell ◽  
Ribonucleic Acids ◽  
Atherosclerosis Progression ◽  
Functional Studies ◽  
Non Coding Rnas ◽  
Atherosclerosis Development

AbstractInflammation plays a pivotal role in the chronicity of atherosclerotic lesion development and progression. Myeloid cells are involved in all stages of atherosclerosis development: they contribute in early phases to endothelial dysfunction and create a pro-inflammatory environment responsible for disease progression. Numerous studies over the last decade have repeatedly provided evidence for the crucial importance for different classes of non-coding ribonucleic acids (RNAs) in regulating gene expression, as well as messenger RNA and protein stability. Functional studies using tools to either over-express or inhibit these non-coding RNAs showcased strong effects on tempering vascular inflammation and atherosclerosis progression. With this current review article, we want to discuss prominent examples of non-coding RNAs, being either produced by myeloid cells or affecting their recruitment and activity in the context of vascular inflammation, atherosclerosis and consequential diseases (such as myocardial infarction and stroke). All of the discussed transcripts were thoroughly studied in mechanistic explorations, indicating that they have the capability to modulate inflammatory cascades in the vasculature during disease exacerbation.

scholarly journals Modeling IKZF1 lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities

2021 ◽  
Author(s):  
Jason H. Rogers ◽  
Rohit Gupta ◽  
Jaime M. Reyes ◽  
Michael Gundry ◽  
Geraldo Medrano ◽  
...  
Keyword(s):  
Cell Function ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Myeloid Cell ◽  
Prognostic Indicator ◽  
Therapy Resistance ◽  
Dominant Negative ◽  
Lymphoid Leukemia ◽  
Increased Risk

IKAROS family zinc finger 1 (IKZF1) alterations represent a diverse group of genetic lesions that are associated with an increased risk of relapse in B-lymphoblastic leukemia (B-ALL). Due to the heterogeneity of concomitant lesions, it remains unclear how IKZF1 abnormalities directly affect cell function and therapy resistance and whether their consideration as a prognostic indicator is valuable in improving outcome. We used CRISPR/Cas9 to engineer multiple panels of isogeneic lymphoid leukemia cell lines with a spectrum of IKZF1 lesions in order to measure changes in chemosensitivity, gene expression, cell cycle, and in vivo engraftment that can be linked to loss of IKAROS protein. IKZF1 knockout and heterozygous null cells displayed relative resistance to a number of common therapies for B-ALL including dexamethasone, asparaginase, and daunorubicin. Transcription profiling revealed a stem/myeloid cell-like phenotype and JAK/STAT upregulation after IKAROS loss. We also used a CRISPR homology-directed repair (HDR) strategy to knock-in the dominant-negative IK6 isoform into the endogenous locus and observed a similar drug resistance profile with the exception of retained dexamethasone sensitivity. Interestingly, IKZF1 knockout and IK6 knock-in cells both have significantly increased sensitivity to cytarabine, likely owing to marked downregulation of SAMHD1 after IKZF1 knockout. Both types of IKZF1 lesions decreased survival time of xenograft mice, with higher numbers of circulating blasts and increased organ infiltration. Given these findings, exact specification of IKZF1 status in patients may be a beneficial addition to risk stratification and could inform therapy.

Abstract 101: Chemerin, A Novel Adipokine, Regulates Human Vascular Cell Function Through Redox-sensitive Processes Involving NADPH Oxidase 1/4 And Endothelial Nitric Oxide Sinthase.

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Karla B Neves ◽  
Rheure A Lopes ◽  
Aurelie D Nguyen ◽  
Nubia S Lobato ◽  
Ana Maria Oliveira ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Injury ◽  
Cell Function ◽  
Vascular Inflammation ◽  
Inflammatory Cells ◽  
Mapk Signaling ◽  
Ros Generation ◽  
Mrna Levels ◽  
Vascular Cells ◽  
H 41

Adipose tissue produces many adipokines, including chemerin, a chemoattractant for inflammatory cells that mediates its effects through chemokine-like receptor 1 (CMKLR1). Chemerin has been implicated in endothelial dysfunction and vascular inflammation, hallmarks of vascular injury in hypertension. These pathological processes are induced by reactive oxygen species (ROS). How chemerin regulates ROS is unknown. We postulated that chemerin, through redox-sensitive mechanisms, influences signalling in vascular cells. Human vascular smooth muscle cells (HVSMCs) and microvascular endothelial cells (HMECs) were studied. HVSMCs and HMECs were stimulated with recombinant chemerin (50ng/ml). eNOS and MAPK activation were assessed by immmunoblotting, ROS generation by chemiluminescence and nitric oxide (NO) levels by DAF-FM fluorescence. mRNA expression of Nox 1, Nox 4 and inflammatory markers was assessed by real time PCR. Chemerin stimulated ROS generation in HVSMCs (1 h - 21% increase; 8 h - 41% increase) and HMECs(1 h - 54% increase; 24 h - 76% increase, p<0.05 vs vehicle), effects blocked by Nox1/4 inhibitor (GKT137831) and Nox1 inhibitor (ML171). Chemerin also increased phosphorylation of ERK1/2 (43% and 62%), p38MAPK (18% and 25%) and JNK (59% and 73%) in HVSMCs and HMECs respectively. eNOS phosphorylation (Ser1177, activation site) was decreased by chemerin in HMECs (45% decrease), while phosphorylation at nhibitory site, Thr495, was increased (72%). In parallel, chemerin decreased NO levels in HMECs by 33%. Finally, chemerin increased IL-6 (290%), MCP-1 (64%), VCAM-1 (210%) and ICAM-1 (130%) mRNA levels in HVSMCs. Nox 1 (49%) and Nox 4 (67%) mRNA levels were increased in HVSMCs stimulated with chemerin. In conclusion in human vascular cells, chemerin stimulates ROS generation and reduces NO formation, through Nox1/4 activation and eNOS inhibition respectively. These processes were associated with increased redox-sensitive MAPK signaling and inflammation. Our study identifies chemerin as a new vasoactive factor, that plays an important role in vascular injury and dysfunction, which may be particularly important in the context of increased adipocyte-derived chemerin, such as in obesity, metabolic syndrome and hypertension.

scholarly journals Endotoxinemia Accelerates Atherosclerosis via Electrostatic Charge-Mediated Monocyte Adhesion

Circulation ◽  
2020 ◽  
Author(s):  
Ariane Schumski ◽  
Almudena Ortega-Gómez ◽  
Kanin Wichapong ◽  
Carla Winter ◽  
Patricia Lemnitzer ◽  
...  
Keyword(s):  
Vascular Inflammation ◽  
Acute Infection ◽  
Atherosclerotic Lesion ◽  
Myeloid Cell ◽  
Lesion Size ◽  
Histone H2a ◽  
Monocyte Adhesion ◽  
Arterial Lumen ◽  
Lps Treatment

Background: Acute infection is a well-established risk factor of cardiovascular inflammation increasing the risk for a cardiovascular complication within the first weeks after infection. However, the nature of the processes underlying such aggravation remains unclear. Lipopolysaccharide (LPS) derived from Gram-negative bacteria is a potent activator of circulating immune cells including neutrophils, which foster inflammation through discharge of neutrophil extracellular traps (NETs). Here we utilize a model of endotoxinemia to link acute infection and subsequent neutrophil activation with acceleration of vascular inflammation. Methods: Acute infection was mimicked by injection of a single dose of LPS into hypercholesterolemic mice. Atherosclerosis burden was studied by histomorphometric analysis of the aortic root. Arterial myeloid cell adhesion was quantified by intravital microscopy. Results: LPS treatment rapidly enhanced atherosclerotic lesion size by expansion of the lesional myeloid cell accumulation. LPS treatment led to the deposition of NETs along the arterial lumen and inhibition of NET release annulled lesion expansion during endotoxinemia, thus suggesting that NETs regulate myeloid cell recruitment. To study the mechanism of monocyte adhesion to NETs, we employed in vitro adhesion assays and biophysical approaches. In these experiments, NET-resident histone H2a attracted monocytes in a receptor-independent, surface charge-dependent fashion. Therapeutic neutralization of histone H2a by antibodies or by in silico designed cyclical peptides enables us to reduce luminal monocyte adhesion and lesion expansion during endotoxinemia. Conclusions: Our study shows, that NET-associated histone H2a mediates charge-dependent monocyte adhesion to NETs and accelerates atherosclerosis during endotoxinemia.

Estrogen Restores Endothelial Cell Function in an Experimental Model of Vascular Injury

Circulation ◽  
1997 ◽  
Vol 96 (5) ◽  
pp. 1624-1630 ◽  
Author(s):  
C. Roger White ◽  
Jonathan Shelton ◽  
Shi-Juan Chen ◽  
Victor Darley-Usmar ◽  
Leslie Allen ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Experimental Model ◽  
Vascular Injury ◽  
Cell Function ◽  
Endothelial Cell Function

scholarly journals Vascular Inflammation and Dysfunction in Lupus-Prone Mice-IL-6 as Mediator of Disease Initiation

2021 ◽  
Vol 22 (5) ◽  
pp. 2291
Author(s):  
Paul Marczynski ◽  
Myriam Meineck ◽  
Ning Xia ◽  
Huige Li ◽  
Daniel Kraus ◽  
...  
Keyword(s):  
Risk Factors ◽  
Lupus Erythematosus ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Intima Media Thickness ◽  
Leukocytic Infiltration ◽  
Increased Risk ◽  
Altered Immune Status ◽  
Inflammatory Autoimmune Disease ◽  
Excellent Tool

Background: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and patients are under an increased risk for cardiovascular (CV) events and mortality. The increased CV risk for patients with SLE seems to be caused by a premature and accelerated atherosclerosis, attributable to lupus-specific risk factors (i.e., increased systemic inflammation, altered immune status), apart from traditional CV risk factors. To date, there is no established experimental model to explore the pathogenesis of this increased CV risk in SLE patients. Methods: Here we investigated whether MRL-Faslpr mice, which develop an SLE-like phenotype, may serve as a model to study lupus-mediated vascular disease. Therefore, MRL-Faslpr, MRL-++, and previously generated Il6−/− MRL-Faslpr mice were used to evaluate vascular changes and possible mechanisms of vascular dysfunction and damage. Results: Contrary to MRL-++ control mice, lupus-prone MRL-Faslpr mice exhibited a pronounced vascular and perivascular leukocytic infiltration in various organs; expression of pro-inflammatory cytokines in the aorta and kidney was augmented; and intima-media thickness of the aorta was increased. IL-6 deficiency reversed these changes and restored aortic relaxation. Conclusion: Our findings demonstrate that the MRL-Faslpr mouse model is an excellent tool to investigate vascular damage in SLE mice. Moreover, IL-6 promotes vascular inflammation and damage and could potentially be a therapeutic target for the treatment of accelerated arteriosclerosis in SLE.

scholarly journals AB0473 “HALO SIGN” IN ULTRASOUND OF TEMPORAL, FACIAL AND AXILLARY ARTERIES: ASSOCIATIONS WITH CLINICAL SYMPTOMATOLOGY AND LABORATORY FINDINGS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1534.2-1535
Author(s):  
G. Evangelatos ◽  
G. E. Fragoulis ◽  
A. Iliopoulos
Keyword(s):  
Vessel Wall ◽  
Vascular Inflammation ◽  
Inflammation Markers ◽  
Laboratory Findings ◽  
Clinical Symptomatology ◽  
Temporal Arteries ◽  
Halo Sign ◽  
Increased Risk ◽  
Us Findings ◽  
Specific Symptoms

Background:Giant cell arteritis (GCA) has two subtypes, the cranial form (“cranial GCA”) and the large-vessel form (“LV-GCA”). GCA can present with “cranial” symptoms (headache, visual symptoms, jaw claudication, scalp tenderness), constitutional symptoms (fever, fatigue), limb claudication and symptoms of polymyalgia rheumatica (PMR) and usually causes increased inflammation markers, anemia and thrombocytosis. Ultrasound (US) of the temporal and axillary arteries has a well-established role in cranial GCA and LV-GCA diagnosis, respectively. However, it is unknown whether specific clinical and laboratory parameters are linked with US findings suggestive of vascular inflammation (“halo” sign).Objectives:The aim of this study was to examine possible association between clinical and laboratory characteristics of the patients and detection of vessel wall inflammation in the US.Methods:Patients ≥50 years old with elevated ESR (≥50mm/h) and/or CRP (≥10mg/L) that presented in our outpatient rheumatology clinics from July 2017 to December 2019 with possible clinical diagnosis of GCA were included. Three groups were compared: Patients with “cranial symptoms” (with or without PMR), patients with PMR symptoms only and patients with increased inflammation markers without specific symptoms indicative of GCA. Temporal arteries and their main branches, as well as facial and axillary arteries were evaluated by US bilaterally for the presence of non-compressible “halo sign” at the vessel wall. Clinical symptomatology and the occurrence of anemia and thrombocytosis were recorded.Results:52 patients were included. 71.2% were females, with a mean±SD age of 71.0±10.0 years. 17 patients had “cranial symptoms” (seven patients with concomitant PMR and ten without), 17 patients had PMR symptoms only, while 18 patients had non-specific symptoms (e.g. fever) (Table 1). Among 17 patients with “cranial symptoms”, 7/7 (100%) with concomitant PMR had a positive temporal US, while only 3 out of 10 (30%) without PMR had a positive temporal US (p<0.01) and US was indeterminate in 2 of them (20%). Collectively, 10/17 (58.8%) of patients with “cranial symptoms” and systemic inflammation had a US examination compatible with GCA. No patient with “cranial symptoms” had a positive US of axillary arteries. No patient with only PMR symptoms, had “halo sign” in temporal and facial arteries, while 3 out of 17 (17.6%) had a positive axillary US. From the 18 patients with elevated ESR/CRP, one had a positive temporal US and another one had a positive axillary US. Regarding specific symptoms, positive temporal US was associated with new headache (p=0.003), vision impairment (p=0.001), jaw claudication (p=0.05), scalp tenderness (p=0.01) and fever (P=0.002), but not with PMR (p=0.317). Thrombocytosis was associated with an increased risk for “halo sign” detection in temporal (p=0.04) and facial (p=0.007) arteries, but not in axilliary arteries (p=0.52).Conclusion:60% of patients with “cranial symptoms” and elevated inflammation markers have US temporal findings indicative of GCA. This is more pronounced in patients with concomitant PMR symptoms and is associated with specific symptomatology. 18% of patients with only PMR symptoms might have LV-GCA, while those with high ESR/CRP without GCA-related symptoms rarely have “halo sign” in US.Disclosure of Interests:None declared

scholarly journals Regulation of Myeloid Cell Function through the CD200 Receptor

2005 ◽  
Vol 176 (1) ◽  
pp. 191-199 ◽  
Author(s):  
Maria C. Jenmalm ◽  
Holly Cherwinski ◽  
Edward P. Bowman ◽  
Joseph H. Phillips ◽  
Jonathon D. Sedgwick
Keyword(s):  
Cell Function ◽  
Myeloid Cell ◽  
Cd200 Receptor

Abstract O.29: Transcriptional Profiling Discriminates Complete and Incomplete KD from Human Adenovirus

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Preeti Jaggi ◽  
Asuncion Mejias ◽  
Adriana Tremoulet ◽  
Jane Burns ◽  
Wei Wang ◽  
...  
Keyword(s):  
Transcriptional Profiling ◽  
Myeloid Cell ◽  
Human Adenovirus ◽  
Response To Therapy ◽  
Transcriptional Analysis ◽  
Coagulation Cascade ◽  
Prediction Algorithm ◽  
Prognostic Information ◽  
Class Prediction ◽  
Modular Analysis

Background: The diagnosis of Kawasaki disease (KD) is often difficult to distinguish from HAdV. Objective: 1) To characterize the specific transcriptional profiles of KD patients versus acute HAdV infection 2) To determine whether the molecular distance to health (MDTH) score (a molecular score that reflects the perturbation derived from whole genome transcriptional analysis) correlates with response to therapy. Methods: Whole blood RNA samples collected in Tempus tubes were analyzed using Illumina chips and GeneSpring software 7.4 from 76 pediatric patients with complete KD, 13 with incomplete KD, and 19 patients with HadV, and 20 age- and sex-matched healthy controls (HC). We used class comparison algorithms (Mann-Whitney p< 0.01, Benjamini-Hochberg, and 1.25- fold change filter) and modular analysis to define the KD profiles; class prediction algorithm was used to identify genes that best differentiate KD and HAdV. Results: Statistical group comparisons identified 7,899 genes differentially expressed in 39 complete KD patients versus HC (KD biosignature). This signature was validated in another 37 patients with complete KD and in 13 patients with incomplete KD. Modular analysis in children with complete KD demonstrated overexpression of inflammation, neutrophils, myeloid cell, coagulation cascade, and cell cycle genes. The class prediction algorithm identified 25-classifier genes that differentiated children with KD vs HAdV infection in two independent cohorts of patients with 92% (95% CI [73%-99%]) sensitivity and 90% [67%-98%] specificity. MDTH scores in KD patients significantly correlated with the baseline c-reactive protein (R=0.29, p=0.008) and was four fold higher than in children with HAdV (p<0.01). In addition, KD patients that remained febrile 36 hours after treatment with IVIG (non-responders) demonstrated higher baseline, pre-treatment MDTH values compared with responders [12,290 vs. 5572 respectively; p=0.009]. Conclusion: Transcriptional signatures can be used as a tool to discriminate between KD and HAdV infection, and may also provide prognostic information.

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