scholarly journals ApoL6: A Novel Biomarker of Apoptotic Activity in Evolving ST-segment Myocardial Infarction in Man

2020 ◽  
pp. 1-2
Author(s):  
Chien-An Andy Hu ◽  
Chien-An Andy Hu ◽  
Siqin Zhaorigetu ◽  
W Sean Davidson ◽  
Warren Laskey
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Inflammatory Response ◽  
Proinflammatory Cytokines ◽  
Ectopic Expression ◽  
Cell Types ◽  
Phospholipid Binding ◽  
St Segment ◽  
Apoptotic Activity ◽  
Cell Death Phenotype

We have previously demonstrated that apolipoprotein L6 (ApoL6) is a pro-death, phospholipid-binding, BH3-only member of the Bcl-2 family. Ectopic expression of ApoL6 induces dichotomous cell death phenotype involving both apoptosis and necroptosis in various cell types. In addition, ApoL6 initiates inflammatory response that upregulates proinflammatory cytokines, such as IL-1β. In this study, we show elevated levels of ApoL6 in the sera of the majority of ST-segment myocardial infarction (STEMI) patients prior to reperfusion which is highly suggestive of the activation of apoptotic and/or necroptotic pathways in ruptured plaque. Thus, ApoL6 could serve as a biomarker specific for inflammatory apoptotic and/or necroptotic activity in STEMI, as well as other diseases.

scholarly journals TNFα-induced AMPA-receptor trafficking in CNS neurons; relevance to excitotoxicity?

2004 ◽  
Vol 1 (3) ◽  
pp. 263-273 ◽  
Author(s):  
DMITRI LEONOUDAKIS ◽  
STEVEN P. BRAITHWAITE ◽  
MICHAEL S. BEATTIE ◽  
ERIC C. BEATTIE
Keyword(s):  
Cell Death ◽  
Inflammatory Response ◽  
Hippocampal Neurons ◽  
Neuronal Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Cell Types ◽  
Synaptic Function ◽  
Ampar Trafficking ◽  
Novel Target

Injury and disease in the CNS increases the amount of tumor necrosis factor α (TNFα) that neurons are exposed to. This cytokine is central to the inflammatory response that occurs after injury and during prolonged CNS disease, and contributes to the process of neuronal cell death. Previous studies have addressed how long-term apoptotic-signaling pathways that are initiated by TNFα might influence these processes, but the effects of inflammation on neurons and synaptic function in the timescale of minutes after exposure are largely unexplored. Our published studies examining the effect of TNFα on trafficking of AMPA-type glutamate receptors (AMPARs) in hippocampal neurons demonstrate that glial-derived TNFα causes a rapid (<15 minute) increase in the number of neuronal, surface-localized, synaptic AMPARs leading to an increase in synaptic strength. This indicates that TNFα-signal transduction acts to facilitate increased surface localization of AMPARs from internal postsynaptic stores. Importantly, an excess of surface localized AMPARs might predispose the neuron to glutamate-mediated excitotoxicity and excessive intracellular calcium concentrations, leading to cell death. This suggests a new mechanism for excitotoxic TNFα-induced neuronal death that is initiated minutes after neurons are exposed to the products of the inflammatory response.Here we review the importance of AMPAR trafficking in normal neuronal function and how abnormalities that are mediated by glial-derived cytokines such as TNFα can be central in causing neuronal disorders. We have further investigated the effects of TNFα on different neuronal cell types and present new data from cortical and hippocampal neurons in culture. Finally, we have expanded our investigation of the temporal profile of the action of this cytokine relevant to neuronal damage. We conclude that TNFα-mediated effects on AMPAR trafficking are common in diverse neuronal cell types and very rapid in their onset. The abnormal AMPAR trafficking elicited by TNFα might present a novel target to aid the development of new neuroprotective drugs.

5947Predictive role of C-reactive protein levels in patients with ST-segment elevation acute myocardial infarction for heart failure related events

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
B Van Tassell ◽  
C R Trankle ◽  
D Kadariya ◽  
J M Canada ◽  
S Carbone ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Multivariate Analysis ◽  
Inflammatory Response ◽  
Composite Endpoint ◽  
The United States ◽  
C Reactive Protein ◽  
St Segment Elevation ◽  
Reactive Protein ◽  
St Segment

Abstract Background ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). C-reactive protein (CRP) is the inflammatory biomarker most commonly used for risk stratification in patients with cardiovascular diseases. CRP levels are known to rise and fall during STEMI in response to myocardial injury. In this study, we analyzed whether admission CRP or delayed CRP (measured at 72 hours after admission) held a greater predictive value for adverse HF events in patients with STEMI. Methods We analyzed data from the VCUART3 clinical trial enrolling 99 patients with STEMI within 12 hours of presentation at 3 sites in the United States of America treated with anakinra or placebo. CRP levels were measured with a high-sensitivity assay at time of admission and again at 72 hours later. A dedicated committee composed of individuals not involved in the conduct of the trial adjudicated HF events including a composite endpoint of death from any reason or incidence of HF defined as new-onset HF requiring hospital admission or a new prescription for a loop diuretic (D+HF) and a composite endpoint of death and HF hospitalization (D+HHF) at 1 year. We used a time-dependent Cox-regression analysis to determine the association of CRP at admission or at 72 hours with the outcomes of interest in univariate and multivariate analysis. Data are presented as median and interquartile range. (ClinicalTrials NCT01950299) Results CRP levels from admission and 72 hours were available in 90 and 87 subjects respectively and they increased from 4.6 [2.8–8.5] mg/L to 11.6 [4.6–24.5] mg/L (P<0.001). Both admission CRP (CRP0) and CRP at 72 hours (CRP72) were associated with the risk of D+HF (P=0.011 and <0.001, respectively) and of D+HHF (P=0.010 and P<0.001, respectively); however at multivariate analysis, only CRP72 remained significantly associated with the risk of D+HF (P=0.001) and D+HHF (P=0.004) while CRP0 was not. CRP72 significantly correlated with NTproBNP levels at 72 hours (NTproBNP72, Spearman rho R=+0.37, P=0.001). NTproBNP72 predicted D+HF (P=0.030) but not independently of CRP72 (P=0.096 for NTproBNP72 and P=0.007 for CRP72 at multivariate analysis including the 2 variables). NTproBNP72 did not predict D-HHF. Conclusions Among contemporary patients with STEMI, the levels of CRP at 72 hours after admission was superior to admission CRP levels for predicting the incidence of HF events, and independent of NTproBNP levels. Our results indicate the importance of the inflammatory response during STEMI, supporting the concept of inhibiting the inflammatory response as a therapeutic strategy. Acknowledgement/Funding Funded by NHLBI 1R34HL121402; Drug supply from Swedish Orphan Biovitrum

CD34+CXCR4+ Cell Therapy (AMR-001) for Myocardial Infarction: Preliminary Processing and Product Results of a Phase I Dose Escalation Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 773-773
Author(s):  
Ned Waller ◽  
Arshed Quyyumi ◽  
Douglas Vaughan ◽  
Thomas Moss ◽  
Wai S. Chan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Cell Death ◽  
Phase I ◽  
Ventricular Remodeling ◽  
Phase 1 ◽  
Myocardial Cell ◽  
Infarct Zone ◽  
St Segment ◽  
Cd34 Cells

Abstract Background: Approximately 20% of patients suffering a ST segment elevated acute myocardial infarction (AMI) have progressive peri-infarct zone myocardial cell death causing ventricular remodeling and poor cardiac outcomes in spite of large vessel revascularization and medical management. Neo-angiogenesis occurs when VEGF levels peak and endothelial precursors are mobilized and recruited to the infarct site. Stromal cell derived factor-1 (SDF-1), the ligand for the CXCR4 receptor, is expressed by CD34+ cells and plays a role in cell homing to areas of ischemic damage. CD34+ CXCR4+ cells home to areas of ischemia, rich in SDF-1, including infarcted myocardium and are capable of inducing neo-angiogenesis. Natural neoangiogenesis is present but insufficient following AMI, suggesting that direct administration of CD34+ CXCR4+ progenitors could mitigate peri-infarct zone myocardial cell death and improve ventricular function. Methods: In this phase I study, patients with an ST segment (AMI) are enrolled in cohorts of 5 to receive one of four doses (5, 10, 15, 20 x 106 of bone marrow derived CD34+ cells. Cells are harvested using a mini-bone marrow harvest (MMH) technique, acquired by Isolex selection and administered by infusion via the infarct related artery 5 to 10 day following successful coronary artery stenting post AMI. The first 10 subjects accrued as subjects on this phase 1 study included 9 males and 1 female, with a median age of 52 years (range 36–70). Results: The first ten patients (of 20 planned) underwent a MMH under conscious sedation without incident. Adequate numbers of viable, enriched CD34+ cells were obtained following Isolex selection for treatment of subjects enrolled at the first two dose cohorts (5 x 106 and 10 x 106 CD34+ cells). The mean fraction of cells expressing CD34 in the marrow product was 0.75%, with a mean recovery of 40% following Isolex selection (Table). Conclusions: Our study demonstrates the feasibility of collecting up to 409 ml of bone marrow using a MMH technique in the immediate post AMI setting, with yields up to 86 x 106 CD34+ cells. All patient cells expressed CXCR4 and had in vitro migratory capacity. However the lower than expected percentage of TNC expressing CD34 (compared with 9 healthy age matched individuals (1.49% vs. 0.75%) and a low % recovery following Isolex selection may limit successful upper (>10 x 106) cohort treatments. VEGf-2 expression on enriched CD34+ cells was variable. Processing and Product Results (N=10) mean (median) range *N=7 (technical loss of 3 samples);** N=9 (technical loss of 1 sample) MMH marrow volume (ml) 395 (396) 377 – 409 Harvest TNC content (x 109) 6.65 ( 6.73) 3.85 – 8.59 Harvest CD34+ content (x 106) 45.3 (50.2) 16.9 – 86.7 Harvest CD34+ % of TNC 0.75% (0.72%) 0.54% – 1.06% Selected CD34+ content (x 106) 17.8 (16.5) 8.4 – 28.9 Selected % CD34+ recovery 40.3% (41.9%) 30.2 – 49.7 Selected %CD34+ viability 97.1% (98.0 %) 96% – 99% Selected % CD34+ purity 82.5% (84.%) 70% – 91% Total processing time (hours) 14.2 (14.0) 11 – 17 SDF-1 induced migration (% of CD34+ cells) 20.2% (17.0%) 9.5% – 35.4% CXCR-4 expression(% of CD34+ cells)* 58.7% (52.0%) 44% – 78% VEGF-2 expression (% of CD34+ cells)** 0.82% (0.86%) 0% – 2.39%

scholarly journals Anticancer Drugs Up-regulate HspBP1 and Thereby Antagonize the Prosurvival Function of Hsp70 in Tumor Cells

2007 ◽  
Vol 282 (49) ◽  
pp. 35430-35439 ◽  
Author(s):  
Susumu Tanimura ◽  
A-i Hirano ◽  
Junya Hashizume ◽  
Masahiro Yasunaga ◽  
Takumi Kawabata ◽  
...  
Keyword(s):  
Cell Death ◽  
Heat Shock ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Anticancer Drugs ◽  
Ectopic Expression ◽  
Biological Significance ◽  
Cell Types ◽  
Molar Ratio ◽  
Lysosomal Membranes

The 70-kDa heat shock protein (Hsp70) is up-regulated in a wide variety of tumor cell types and contributes to the resistance of these cells to the induction of cell death by anticancer drugs. Hsp70 binding protein 1 (HspBP1) modulates the activity of Hsp70 but its biological significance has remained unclear. We have now examined whether HspBP1 might interfere with the prosurvival function of Hsp70, which is mediated, at least in part, by inhibition of the death-associated permeabilization of lysosomal membranes. HspBP1 was found to be expressed at a higher level than Hsp70 in all normal and tumor cell types examined. Tumor cells with a high HspBP1/Hsp70 molar ratio were more susceptible to anticancer drugs than were those with a low ratio. Ectopic expression of HspBP1 enhanced this effect of anticancer drugs in a manner that was both dependent on the ability of HspBP1 to bind to Hsp70 and sensitive to the induction of Hsp70 by mild heat shock. Furthermore, anticancer drugs up-regulated HspBP1 expression, whereas prevention of such up-regulation by RNA interference reduced the susceptibility of tumor cells to anticancer drugs. Overexpression of HspBP1 promoted the permeabilization of lysosomal membranes, the release of cathepsins from lysosomes into the cytosol, and the activation of caspase-3 induced by anticancer drugs. These results suggest that HspBP1, by antagonizing the prosurvival activity of Hsp70, sensitizes tumor cells to cathepsin-mediated cell death.

scholarly journals Association of Circulating, Inflammatory-Response Exosomal mRNAs With Acute Myocardial Infarction

2021 ◽  
Vol 8 ◽  
Author(s):  
Guo-dong He ◽  
Yu-qing Huang ◽  
Lin Liu ◽  
Jia-yi Huang ◽  
Kenneth Lo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Inflammatory Response ◽  
Immune Cell ◽  
Stable Coronary Artery Disease ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Diagnostic Value ◽  
Acute Inflammatory Response ◽  
Clinical Value

Background: Although many cardiovascular disease studies have focused on the microRNAs of circulating exosomes, the profile and the potential clinical diagnostic value of plasma exosomal long RNAs (exoLRs) are unknown for acute myocardial infarction (AMI).Methods: In this study, the exoLR profile of 10 AMI patients, eight stable coronary artery disease (CAD) patients, and 10 healthy individuals was assessed by RNA sequencing. Bioinformatic approaches were used to investigate the characteristics and potential clinical value of exoLRs.Results: Exosomal mRNAs comprised the majority of total exoLRs. Immune cell types analyzed by CIBERSORT showed that neutrophils and monocytes were significantly enriched in AMI patients, consistent with clinical baseline values. Biological process enrichment analysis and co-expression network analysis demonstrated neutrophil activation processes to be enriched in AMI patients. Furthermore, two exosomal mRNAs, ALPL and CXCR2, were identified as AMI biomarkers that may be useful for evaluation of the acute inflammatory response mediated by neutrophils.Conclusions: ExoLRs were assessed in AMI patients and found to be associated with the acute inflammatory response mediated by neutrophils. Exosomal mRNAs, ALPL and CXCR2, were identified as potentially useful biomarkers for the study of AMI.

scholarly journals Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis After Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 141 (13) ◽  
pp. 1080-1094 ◽  
Author(s):  
Gopalkrishna Sreejit ◽  
Ahmed Abdel-Latif ◽  
Baskaran Athmanathan ◽  
Rahul Annabathula ◽  
Ashish Dhyani ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Coronary Syndrome ◽  
Inflammatory Response ◽  
Cardiac Function ◽  
Cell Types ◽  
Interleukin 1Β ◽  
Primary Role ◽  
Coronary Syndrome ◽  
Pyrin Domain ◽  
Receptor Family

Background: Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear. Methods: Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI. Results: Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes. Conclusions: Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.

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