scholarly journals ABCA1, TCF7, NFATC1, PRKCZ and PDGFA DNA methylation as potential epigenetic-sensitive targets in acute coronary syndrome via network analysis

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
T Infante ◽  
M Franzese ◽  
A Ruocco ◽  
C Schiano ◽  
O Affinito ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Acute Coronary Syndrome ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Molecular Data ◽  
Aberrant Methylation ◽  
National Budget ◽  
Coronary Syndrome ◽  
Differentially Methylated Genes

Abstract Background Acute coronary syndrome (ACS) is the most severe clinical manifestation of coronary heart disease and the leading cause of death worldwide. Purpose To perform an epigenome-wide analysis in circulating CD4+ and CD8+ T cells of ACS patients and healthy subjects (HS) enrolled in the DIANA clinical trial (NCT04371809) in order to identify differentially methylated genes (DMGs). Methods Genomic DNA was extracted from CD4+ and CD8+ T cells of all subjects and sequenced by the reduced representation bisulfite sequencing (RRBS) platform. Functional pathway analysis was performed and significant DMGs were selected for gene expression validation by qRT-PCR in ACS patients and HS. GeneMANIA was used to built a prediction gene network. Correlation analyses between molecular data and clinical variables were performed. Results In CD4+ T cells we identified 61 differentially methylated regions (DMRs) associated to 57 annotated genes of which 53% (n=32) were hyper- and 47% (n=29) were hypo-methylated in ACS patients vs HS. In CD8+ T cells we identified 613 DMRs associated to 569 annotated genes of which 28% (n=173) were hyper- and 72% (n=440) were hypo-methylated between two groups. In both cell type of ACS patients, 175 DMRs were associated to 157 annotated genes of which 41% (n=72) were hyper- and 59% (n=103) were hypo-methylated. From functional analysis, we selected the top 5 DMGs in the prevalent pathways with the highest differential of methylation values. Specifically, we considered 6 hub genes: NFATC1, TCF7, PDGFA, PRKCB, PRKCZ and ABCA1 and determined their respective expression levels by q-RT-PCR. We found a significant up-regulation of the selected genes in ACS patients vs HS (P<0.001 for all comparisons). Correlation analysis showed both common and cell specific correlation patterns. In CD4+ T cells, PDGFA promoter methylation was negatively correlated with CK-MB concentrations (r=−0.79, P=0.018). ABCA1, TCF7, PDGFA and PRKCZ gene expression was positively associated to CK-MB concentrations (r=0.75, P=0.03; r=0.760, P=0.029; r=0.72, P=0.044; r=0.74, P=0.035, respectively). Conlusions This study is the first single-base resolution map of DNA methylome by RRBS in CD4+ and CD8+ T cells, providing specific methylation signatures that could help to clarify the role of aberrant methylation in ACS pathogenesis, and provide the basis for the search of novel epigenetic-sensitive biomarkers in the prevention and early diagnosis of this pathology. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health;Italian Ministry of Research and University

Abstract 4008: PSGL-1-Expressing CD4 T Cells are Enriched in Culprit Coronary Artery Lesion of Acute Coronary Syndrome

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Keiko Gomita ◽  
Kayoko Sato ◽  
Kazutaka Kitamura ◽  
Nobuhisa Hagiwara
Keyword(s):  
T Cells ◽  
Acute Coronary Syndrome ◽  
Coronary Artery ◽  
Adhesion Molecules ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Coronary Artery Lesion ◽  
Plaque Instability ◽  
Coronary Syndrome

Background: Recently, several evidences on the crucial role of adhesion molecules in the development of atherosclerosis and plaque instability have been reported. While expression of VCAM-1, ICAM-1 and L-selectin has been consistently observed in atherosclerotic plaques it is still uncertain how adhesion molecules on T cells contribute to the incidence of acute coronary syndrome (ACS). In this study, we examined whether adhesion molecules on T cells in ACS have a significant role in the plaque stability and prone to cause ACS. Methods and Results: Fresh CD4 T cells were isolated from the peripheral blood of 76 ACS patients (AMI=35, UAP=41) and 74 age-matched controls (NC). CD69, an activation marker of T cells, was strongly expressed on CD4 T cells from ACS than from NC by FACS (P<0.0001). CD4 T cells from ACS highly expressed p-selectin glycoprotein ligand-1 (PSGL-1) and integrin β (CD18), but not L-selectin by FACS (P < 0.03, P < 0.01, n.s., respectively). Soluble PSGL-1 (sPSGL-1) levels in plasma were lower in ACS patients than in NC (P=0.0001), which correlated negatively with the PSGL-1 expression on CD4 T cells (R=0.405, P<0.02). We further investigated the thrombus-aspirating device samples (n=14) and fresh CD4 T cells derived from both the coronary artery and peripheral blood from the each same patient with ACS. CD4 T cells from the coronary artery strongly expressed PSGL-1 (P<0.002), but not integrin β (CD18) and L-selectin by FACS. Finally, PSGL-1 was expressed on T cells, but not on CD68 positive macrophage, MPO positive neutrophil, or CD41 positive platelets in the thrombus-aspirating device samples. Conclusions: From these results, we demonstrated that PSGL-1-expressing CD4 T cells are enriched in the culprit coronary artery lesion of ACS, contributing to the acceleration of plaque instability and occurrence of ACS.

scholarly journals Premature CD4+ T Cells Senescence Induced by Chronic Infection in Patients with Acute Coronary Syndrome

2020 ◽  
Vol 11 (6) ◽  
pp. 1471
Author(s):  
Ming Cao ◽  
Lei Ruan ◽  
Yi Huang ◽  
Jinli Wang ◽  
Jinhua Yan ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Coronary Syndrome ◽  
Cd4 T Cells ◽  
Chronic Infection ◽  
Coronary Syndrome

scholarly journals Differential transcription directed by discrete gamma interferon promoter elements in naive and memory (effector) CD4 T cells and CD8 T cells.

1997 ◽  
Vol 17 (1) ◽  
pp. 199-208 ◽  
Author(s):  
T M Aune ◽  
L A Penix ◽  
M R Rincón ◽  
R A Flavell
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Transcriptional Activity ◽  
Memory T Cells ◽  
Gamma Interferon ◽  
Ifn Gamma ◽  
Naïve T Cells

Acquisition of the ability to produce gamma interferon (IFN-gamma) is a fundamental property of memory T cells and enables one subset (T helper 1 [TH1]) to deliver its effector functions. To examine regulation of IFN-gamma gene expression in a model system which recapitulates TH1 differentiation, we prepared reporter transgenic mice which express the luciferase gene under the control of proximal and distal regulatory elements (prox.IFN gamma and dist.IFN gamma) from the IFN-gamma promoter. Memory T cells, but not naive T cells, secreted IFN-gamma and expressed both prox.IFN gamma and dist.IFN gamma transcriptional activities. Naive T cells required priming to become producers of IFN-gamma and to direct transcription by these elements. While both CD4+ and CD8+ T cells produced IFN-gamma, only CD4+ T cells expressed prox.IFN gamma transcriptional activity. Induction of transcriptional activity was inhibited by known antagonists of effector T-cell populations. Cyclosporin A inhibited transcriptional activity directed by both elements in effector T cells. Elevated cyclic AMP inhibited transcriptional activity directed by prox.IFN gamma in primed CD4+ T cells but enhanced transcriptional activity directed by dist.IFN gamma in primed CD8+ T cells. Taken together, these data show that prox.IFN gamma and dist.IFN gamma transcriptional activities mirror IFN-gamma gene expression in naive and memory CD4+ T cells but suggest that differences exist in regulation of IFN-gamma gene expression in CD4+ and CD8+ T-cell subsets.

scholarly journals Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study

2020 ◽  
Vol 41 (37) ◽  
pp. 3549-3560 ◽  
Author(s):  
David M Leistner ◽  
Nicolle Kränkel ◽  
Denitsa Meteva ◽  
Youssef S Abdelwahed ◽  
Claudio Seppelt ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Coronary Syndrome ◽  
T Cell ◽  
T Lymphocytes ◽  
Cd8 T Cells ◽  
Coronary Plaque ◽  
Effector Molecules ◽  
Coronary Syndrome ◽  
Fibrous Cap ◽  
Cd8 T Lymphocytes

Abstract Aims  Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping. Methods and results  The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P &lt; 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P &lt; 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS. Conclusions  The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC. Trial registration The study was registered at clinicalTrials.gov (NCT03129503).

scholarly journals P-Selectin Glycoprotein Ligand-1 (PSGL-1) Expressing CD4 T Cells Contribute Plaque Instability in Acute Coronary Syndrome

2018 ◽  
Vol 82 (8) ◽  
pp. 2128-2135 ◽  
Author(s):  
Kazutaka Kitamura ◽  
Kayoko Sato ◽  
Motoji Sawabe ◽  
Masayuki Yoshida ◽  
Nobuhisa Hagiwara
Keyword(s):  
T Cells ◽  
Acute Coronary Syndrome ◽  
Cd4 T Cells ◽  
Plaque Instability ◽  
Coronary Syndrome

The Feature of TCR Zeta Gene in CD4+ and CD8+ T Cells in Patients with CML.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4526-4526
Author(s):  
Si Chen ◽  
Yangqiu Li ◽  
Shaohua Chen ◽  
Lijian Yang ◽  
Xiuli Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Gene Expression Level ◽  
Expression Level ◽  
Chain Gene ◽  
Zeta Chain ◽  
Normal Individuals ◽  
Normal Controls

Abstract The T-cell receptor (TCR) zeta chain is a master sensor and regulator of lymphocyte responses which plays a critical role in TCR-mediated signal transduction. The abnormal expression of TCR zeta gene was found in some malignancies and immune disease. Cellular immune deficiency is the common feature in patients with chronic myeloid leukemia (CML). Our previous studies had showed that 60% of CML patients displayed an abnormally low expression of TCR zeta chain in peripheral blood mononuclear cells (PBMCs). To further estimate the changes of zeta chain expression of T-lymphocyte subsets in CML, TCR zeta chain gene expression level in purified CD4+ and CD8+ T cells sorted by MACS were detected by real-Time PCR with SYBR Green I technique, CD4+ and CD8+ T cells from both 10 cases with CML and 10 normal individuals were selected to analyze in the study. β2 -microglobulin was used as an endogenous reference. Relative changes in TCR zeta gene expression level were used by the 2−ΔCt×100% method. The relative mRNA expression level of TCR zeta gene in CD4+ and CD8+ T cells from CML was 4.06±4.82% and 3.82±4.25% respectively, whereas 7.75±2.52% and 5.19±1.25% were found in normal individuals. There was a wide range in the TCR zeta gene expression level of CD4+ T cells from CML patients (0.23–15.93%,) with a median value of 1.77%, whereas the a range of (4.74–12.81%) with a median of 7.93% was showed in normal controls (P=0.046). The expression level of TCR zeta gene in CD8+ T cells from controls ranged from 3.47% to 6.75% (median 5.52%) and in CML patients from 0.86% to 15.55% with a median of 2.51% (P=0.340). The results indicated that, compared with normal controls, zeta chain gene expression was obviously down-regulated in CD4+ T cells from patients with CML. However, there was not significant different in expression level of TCR zeta gene of CD8+ T cells between CML patients and normal individuals. Moreover, the expression level of TCR zeta gene is nonsignificant age-associated or gender-link in CD4+ T cells and CD8+ T cells from patients with CML. In conclusions, the results provide at first the difference of TCR-zeta gene expression pattern in CD4+ and CD8+ T cells from patients with CML, this may be reflective of signaling difference between the different T cell subtypes in immunodeficiency state of patients.

scholarly journals Decreased Helios Expression in Regulatory T Cells in Acute Coronary Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Lili Jiang ◽  
Feng Chen ◽  
Xiaofan Hu ◽  
Yingying Hu ◽  
Yange Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Coronary Syndrome ◽  
Regulatory T Cells ◽  
Mrna Expression ◽  
Stable Angina ◽  
Cd4 T Cells ◽  
Coronary Syndrome ◽  
Control Subjects ◽  
Bona Fide ◽  
And Control

Regulatory T cells (Tregs) play an essential role in acute coronary syndrome (ACS). However, there is debate about which Treg subsets are truly critical to ACS. Helios, a transcription factor, was recently reported to be a bona fide marker for natural Tregs or activated Tregs with a suppression function, but little is known about its role in ACS. We therefore examined Helios+ Tregs in patients with ACS, patients with stable angina, and control subjects. 73 patients with ACS, 30 patients with stable angina, and 48 control subjects were enrolled. The frequencies and estimated absolute numbers of different Treg subsets in peripheral blood were measured by flow cytometry. Plasma cytokine level was measured by ELISA. The mRNA expression of Foxp3 and Helios in purified CD4+ T cells was determined by RT-PCR. Helios+ Tregs was decreased significantly in patients with ACS. The frequency and estimated absolute numbers of CD4+Foxp3+Helios+ Tregs were negatively correlated with IL-6 and positively correlated with circulating level of TGF-beta1 and HDL-C. The mRNA expression of Foxp3 and Helios was decreased in CD4+ T cells from patients with ACS. In summary, Helios+ Tregs was downregulated in patients with ACS and may play a role in ACS.

CCR5+ CD8 T-cell levels and monocyte activation precede the onset of acute coronary syndrome in HIV-infected patients on antiretroviral therapy

2017 ◽  
Vol 117 (06) ◽  
pp. 1141-1149 ◽  
Author(s):  
Laura Tarancon-Diez ◽  
Rebeca S. De Pablo-Bernal ◽  
Ana I. Alvarez-Ríos ◽  
Isaac Rosado-Sánchez ◽  
Beatriz Dominguez-Molina ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Coronary Syndrome ◽  
Cd8 T Cells ◽  
Monocyte Activation ◽  
Potential Therapeutic Target ◽  
Coronary Syndrome ◽  
Adaptive Immune ◽  
Time Point

SummaryAcute coronary syndrome (ACS) is nowadays one of the leading causes of morbid-mortality in HIV-infected population, but innate and adaptive immune mechanisms preceding this event are unknown. In this work we comprehensively and longitudinally observed, by multi-parametric flow cytometry and following a case-control design, increased CCR5+CD8+ T-cells levels and monocytes expressing activation and adhesion markers in HIV-infected patients who are going to suffer ACS. In addition, we found direct associations between activated CD8+ T-cells and myeloid cells that were only statistically significant in the group of patients with ACS and in the follow up time point just before the ACS. Our data highlight the important role of CCR5 in the onset of ACS and suggest this receptor as a marker of cardiovascular risk and potential therapeutic target to prevent the development of such non-AIDS-related event in HIV-infected patients.Note: This work was presented at the CROI 2016 conference (Boston, USA in February 2016).

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