scholarly journals Tissue distribution and transcriptional regulation of CCN5 in the heart after myocardial infarction

2021 ◽  
Author(s):  
Sima Zolfaghari ◽  
Ole Jørgen Kaasbøll ◽  
M. Shakil Ahmed ◽  
Fabian A. Line ◽  
Else Marie V. Hagelin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Endothelial Cells ◽  
Tissue Distribution ◽  
Pressure Overload ◽  
Firefly Luciferase ◽  
Scar Tissue ◽  
Early Gene ◽  
Ccn Family ◽  
Protein Levels ◽  
Tnf Α

AbstractCCN5 is a divergent member of the cellular communication network factor (CCN) family in that it lacks the carboxyl terminal cystine knot domain common to the other CCN family members. CCN5 has been reported to antagonize the profibrotic actions of CCN2 and to inhibit myocardial collagen deposition and fibrosis in chronic pressure overload of the heart. However, what mechanisms that regulate CCN5 activity in the heart remain unknown. Recombinant, replication defective adenovirus encoding firefly luciferase under control of the human CCN5 promoter was prepared and used to investigate what mechanisms regulate CCN5 transcription in relevant cells. Tissue distribution of CCN5 in hearts from healthy mice and from mice subjected to myocardial infarction was investigated. Contrary to the profibrotic immediate early gene CCN2, we find that CCN5 is induced in the late proliferation and maturation phases of scar healing. CCN5 was identified principally in endothelial cells, fibroblasts, smooth muscle cells, and macrophages. Our data show that CCN5 gene transcription and protein levels are induced by catecholamines via β2-adrenergic receptors. Myocardial induction of CCN5 was further confirmed in isoproterenol-infused mice. We also find that CCN5 transcription is repressed by TNF-α, an inflammatory mediator highly elevated in early phases of wound healing following myocardial infarction. In conclusion, CCN5 predominates in endothelial cells, fibroblasts, and macrophages of the differentiating scar tissue and its transcription is conversely regulated by β2-adrenergic agonists and TNF-α.

scholarly journals Anti-Inflammatory and Anti-Apoptotic Effects of Stybenpropol A on Human Umbilical Vein Endothelial Cells

2019 ◽  
Vol 20 (21) ◽  
pp. 5383 ◽  
Author(s):  
Li Zhang ◽  
Feifei Wang ◽  
Qing Zhang ◽  
Qiuming Liang ◽  
Shumei Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Umbilical Vein ◽  
Caspase 9 ◽  
Protein Levels ◽  
Tnf Α ◽  
Umbilical Vein Endothelial Cells ◽  
Cell Adhesion Molecule 1

Inflammation is a key mediator in the progression of atherosclerosis (AS). Benzoinum, a resin secreted from the bark of Styrax tonkinensis, has been widely used as a form of traditional Chinese medicine in clinical settings to enhance cardiovascular function, but the active components of the resin responsible for those pharmaceutical effects remain unclear. To better clarify these components, a new phenylpropane derivative termed stybenpropol A was isolated from benzoinum and characterized via comprehensive spectra a nalysis. We further assessed how this phenylpropane derivative affected treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α). Our results revealed that stybenpropol A reduced soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-8 (IL-8), and interleukin-1β (IL-1β) expression by ELISA, inhibited apoptosis, and accelerated nitric oxide (NO) release in TNF-α-treated HUVECs. We further found that stybenpropol A decreased VCAM-1, ICAM-1, Bax, and caspase-9 protein levels, and increased the protein levels of Bcl-2, IKK-β, and IκB-α. This study identified a new, natural phenylpropane derivative of benzoinum, and is the first to reveal its cytoprotective effects in the context of TNF-α-treated HUVECs via regulation of the NF-κB and caspase-9 signaling pathways.

Significance of changes in TNF-α and IL-10 levels in the progression of heart failure subsequent to myocardial infarction

2006 ◽  
Vol 291 (1) ◽  
pp. H106-H113 ◽  
Author(s):  
K. Kaur ◽  
A. K. Sharma ◽  
P. K. Singal
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Coronary Artery ◽  
Cardiac Function ◽  
Interleukin 10 ◽  
Mrna Levels ◽  
Protein Ratio ◽  
Protein Levels ◽  
Tnf Α ◽  
Membrane Bound

We tested whether a decrease in the ratio of interleukin-10 (IL-10) to tumor necrosis factor-α (TNF-α) correlates with the decrease in cardiac function in heart failure. It has been suggested that TNF-α plays a role in the progression of heart failure, and the effect of TNF-α in many tissues is modulated by IL-10. Any relation of these two cytokines to heart failure has never been examined. Cardiac function was assessed by echocardiographic and hemodynamic techniques in coronary artery-ligated rats at 1, 4, 8, and 16 wk after myocardial infarction (MI). Membrane-bound and soluble fractions of TNF-α and IL-10 proteins, the ratio of TNF-α to IL-10, and TNF-α and IL-10 mRNA levels were analyzed. Losartan was used to modify cardiac function in rats 4 wk after MI to further validate the relation between the IL-10-to-TNF-α ratio and cardiac function. Cardiac function deteriorated with time in all coronary artery-ligated groups, with severe failure at 16 wk after MI. Membrane-bound and soluble TNF-α protein fractions were increased 1 and 4 wk after MI, whereas TNF -α mRNA was increased 4 and 8 wk after MI. Membrane-bound IL-10 protein and mRNA levels were decreased 4, 8, and 16 wk after MI. The decrease in the IL-10-to-TNF-α protein ratio in all coronary artery-ligated groups correlated with the depressed cardiac function. Losartan improved cardiac function, membrane-bound and soluble TNF-α and IL-10 protein levels, the ratio of IL-10 to TNF-α, and IL-10 mRNA. This study suggests that a decrease in IL-10 and IL-10-to-TNF-α ratio correlates with depressed cardiac function.

MicroRNA-126 contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation

2012 ◽  
Vol 302 (12) ◽  
pp. F1630-F1639 ◽  
Author(s):  
S. A. Ásgeirsdóttir ◽  
C. van Solingen ◽  
N. F. Kurniati ◽  
P. J. Zwiers ◽  
P. Heeringa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Expression ◽  
Molecular Mechanisms ◽  
Molecular Control ◽  
Protein Levels ◽  
Tnf Α ◽  
Inflammatory Stimuli ◽  
Endothelial Cell Adhesion Molecules ◽  
Differential Responsiveness

Endothelial cells in different microvascular segments of the kidney have diverse functions and exhibit differential responsiveness to disease stimuli. The responsible molecular mechanisms are largely unknown. We previously showed that during hemorrhagic shock, VCAM-1 protein was expressed primarily in extraglomerular compartments of the kidney, while E-selectin protein was highly induced in glomeruli only (van Meurs M, Wulfert FM, Knol AJ, de Haes A, Houwertjes M, Aarts LPHJ, Molema G. Shock 29: 291–299, 2008). Here, we investigated the molecular control of expression of these endothelial cell adhesion molecules in mouse models of renal inflammation. Microvascular segment-specific responses to the induction of anti-glomerular basement membrane (anti-GBM), glomerulonephritis and systemic TNF-α treatment showed that E-selectin expression was transcriptionally regulated, with high E-selectin mRNA and protein levels preferentially expressed in the glomerular compartment. In contrast, VCAM-1 mRNA expression was increased in both arterioles and glomeruli, while VCAM-1 protein expression was limited in the glomeruli. These high VCAM-1 mRNA/low VCAM-1 protein levels were accompanied by high local microRNA (miR)-126 and Egfl7 levels, as well as higher Ets1 levels compared with arteriolar expression levels. Using miR-reporter constructs, the functional activity of miR-126 in glomerular endothelial cells could be demonstrated. Moreover, in vivo knockdown of miR-126 function unleashed VCAM-1 protein expression in the glomeruli upon inflammatory challenge. These data imply that miR-126 has a major role in the segmental, heterogenic response of renal microvascular endothelial cells to systemic inflammatory stimuli.

Abstract 362: Acute Exposure to Air Pollution Aggravates Acute Myocardial Infarction and Subsequent Ischemic Heart Failure in Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Dennis Wolf ◽  
Timoteo Marchini ◽  
Nathaly Anto Michel ◽  
Daniel Dürschmied ◽  
Ingo Hilgendorf ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Air Pollution ◽  
Endothelial Cells ◽  
Particulate Matter ◽  
Alveolar Macrophages ◽  
Intravital Microscopy ◽  
Ischemic Heart Failure ◽  
Cell Recruitment ◽  
Tnf Α

Background: Clinical, but not experimental evidence has suggested that exposure to air pollution particulate matter (PM) aggravates myocardial infarction (MI) in humans. Here, we aimed to describe mechanisms and consequences of an acute PM exposure in an experimental mouse model of MI. Methods and Results: C57BL/6J mice were exposed to an air pollution particulate matter (PM) surrogate (Residual Oil Fly Ash) by intranasal installation, prior to surgical permanent ligation of the left anterior descending coronary artery (LAD). Mice exposed to PM showed exaggerated ischemic heart failure with decreased fractional shortening and diastolic dilatation in echocardiography 6 month after MI. Histological analysis demonstrated an increase in the infarct area by 45 ± 12 % and enhanced inflammatory cell recruitment into the myocardium of PM-exposed mice 6 days after MI. Augmented cell recruitment was caused by increased activation of circulating myeloid and vascular endothelial cells. Consistently, PM exposure increased leukocyte recruitment a model of sterile peritonitis and in intravital microscopy. Mechanistically, PM exposure potentiated levels of circulating pro-inflammatory cytokines, such as of TNF-α by up to 327 ± 100 %. Increased activation of endothelial cells and leukocytes could be reversed by TNF-α antibody blockade. We identified alveolar macrophages as primary source of elevated cytokine production. Accordingly, specific in vivo depletion of lung macrophages by clodronate inhibited cytokine secretion, abolished leukocyte recruitment in intravital microscopy, and protected from cardiac inflammation after simultaneous PM exposure. Conversely, lymphocyte-free Rag1 -/- mice where susceptible to PM, indicating that alveolar macrophages, but not lymphocytes, are the cause of the systemic inflammatory response following air pollution. Conclusion: Our data demonstrate that an acute exposure to environmental PM worsens MI and its clinical outcome in mice. These findings provide a novel functional link between air pollution and inflammatory pathways, and emphasize the importance of environmental factors in cardiovascular disease.

Abstract P138: PTEN Mediates Post--Myocardial Infarction Remodeling

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Nirmal Parajuli ◽  
Yuan Yuan ◽  
Djahida Bedja ◽  
Zheqing P Cai
Keyword(s):  
Myocardial Infarction ◽  
Mononuclear Cell ◽  
Cardiac Remodeling ◽  
Cytokine Production ◽  
Cell Infiltration ◽  
Separate Experiment ◽  
Mononuclear Cell Infiltration ◽  
Protein Levels ◽  
Infarct Area ◽  
Tnf Α

Background- Following myocardial infarction (MI), innate immunity is activated, leading to cytokine production and initiation of inflammation. Interleukin (IL)-10 has been reported to attenuate post-MI remodeling by inhibiting expression of tumor necrosis factor (TNF)-α. The phosphatase and tensin homologue deleted on chromosome ten (PTEN) plays an important role in myocardial ischemia-reperfusion injury. It is not known whether PTEN regulates cytokine production and cardiac remodeling. Here, we have investigated the hypothesis that PTEN mediates post-MI remodeling by inhibiting IL-10. Methods and Results- MI was induced in wildtype (WT) mice and Pten heterozygous (HET) mice. In a separate experiment, Pten adenoviruses or empty viruses were injected into the peri-infarct area of WT mice. Left ventricular (LV) anatomical and functional changes were assessed by echocardiography. Mononuclear cell infiltration was measured by histology. TNF-α, IL-10, matrix metalloproteinase (MMP)-2 and MMP-9 protein levels were analyzed in the peri-infarct area. At the end of the experiments, LV end-diastolic diameter (LVEDD) was decreased and fractional shortening (FS) was increased in HET mice compared with WT mice (LVEDD: 4.13±0.22 vs. 5.42±0.26 mm, p<0.01; FS: 21.9±2.6 vs. 11.5±1.1 %, p<0.001). Moreover, heart weight and infarct size were decreased in HET mice compared with WT mice. However, FS was decreased and LV rupture (LVR) was increased in Pten adenovirus-treated mice compared with empty vector-treated mice [FS: 8.2±1.1 vs. 21.5±3.2 %, p < 0.01; LVR: 100% (16/16) vs. 33% (3/9)]. Mononuclear cell infiltration was attenuated in HET mice and worsened in Pten adenovirus-treated mice. IL-10 protein levels were upregulated and TNF-α, MMP-2, and MMP-9 protein levels were downregulated in HET mice. The opposite effects were found in Pten over-expressing hearts. Conclusions- PTEN downregulation increases IL-10 production and inhibits inflammatory responses and attenuates cardiac remodeling; conversely, PTEN over-expression inhibits IL-10 expression and increases cardiac injury. Therefore, our studies demonstrate that PTEN mediates post-MI remodeling, at least in part, by regulating IL-10 production.

Inhibition of Pro-Inflammatory Cytokine Secretion by Select Antioxidants in Human Coronary Artery Endothelial Cells

2020 ◽  
Vol 90 (1-2) ◽  
pp. 103-112 ◽  
Author(s):  
Michael J. Haas ◽  
Marilu Jurado-Flores ◽  
Ramadan Hammoud ◽  
Victoria Feng ◽  
Krista Gonzales ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ascorbic Acid ◽  
Coronary Artery ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Culture Media ◽  
Cytokine Secretion ◽  
Human Coronary Artery ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Abstract. Inflammatory and oxidative stress in endothelial cells are implicated in the pathogenesis of premature atherosclerosis in diabetes. To determine whether high-dextrose concentrations induce the expression of pro-inflammatory cytokines, human coronary artery endothelial cells (HCAEC) were exposed to either 5.5 or 27.5 mM dextrose for 24-hours and interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor α (TNF α) levels were measured by enzyme immunoassays. To determine the effect of antioxidants on inflammatory cytokine secretion, cells were also treated with α-tocopherol, ascorbic acid, and the glutathione peroxidase mimetic ebselen. Only the concentration of IL-1β in culture media from cells exposed to 27.5 mM dextrose increased relative to cells maintained in 5.5 mM dextrose. Treatment with α-tocopherol (10, 100, and 1,000 μM) and ascorbic acid (15, 150, and 1,500 μM) at the same time that the dextrose was added reduced IL-1β, IL-6, and IL-8 levels in culture media from cells maintained at 5.5 mM dextrose but had no effect on IL-1β, IL-6, and IL-8 levels in cells exposed to 27.5 mM dextrose. However, ebselen treatment reduced IL-1β, IL-6, and IL-8 levels in cells maintained in either 5.5 or 27.5 mM dextrose. IL-2 and TNF α concentrations in culture media were below the limit of detection under all experimental conditions studied suggesting that these cells may not synthesize detectable quantities of these cytokines. These results suggest that dextrose at certain concentrations may increase IL-1β levels and that antioxidants have differential effects on suppressing the secretion of pro-inflammatory cytokines in HCAEC.

MicroRNA-16-5p Aggravates Myocardial Infarction Injury by Targeting the Expression of Insulin Receptor Substrates 1 and Mediating Myocardial Apoptosis and Angiogenesis

2020 ◽  
Vol 17 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Xiancan Wang ◽  
Yuqiang Shang ◽  
Shilin Dai ◽  
Wei Wu ◽  
Fan Yi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Viability ◽  
Insulin Receptor ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion ◽  
Nuclear Antigen ◽  
Minichromosome Maintenance ◽  
Protein Levels ◽  
Insulin Receptor Substrates ◽  
Creatine Kinase Mb

Purpose: Myocardial infarction is a common cardiovascular disease. MicroRNA-16-5p (miR-16-5p) was upregulated in heart and kidney hypoxia/reoxygenation (H/R) injury. However, the role of miR-16-5p in myocardial infarction injury is still unclear. Methods: Human adult ventricular cardiomyocytes (AC16) were treated with ischemia/reperfusion (H/R). The miR-16-5p level was evaluated through real-time PCR. The activity of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) was detected via LDH and CK-MB monitoring kits. Cell viability was examined with 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetra-zolium bromide (MTT) assay. Western blotting was used to analyze the protein levels. The luci-ferase report assay confirmed the relative luciferase activity. Results: miR-16-5p was elevated in H/R-treated AC16 cells. miR-16-5p overexpression and knockdown were carried out. miR-16-5p knockdown repressed cell apoptosis, attenuated LDH and CK-MB activities, and enhanced cell viability in H/R-treated AC16 cells. Moreover, miR-16-5p knockdown promoted angiogenesis in human microvascular endothelial cells (HMVEC), causing elevation of vascular endothelial growth factor (VEGF), insulin receptor substrates 1 (IRS1), minichromosome maintenance complex component 2 (MCM2) and proliferating cell nuclear antigen (PCNA) protein levels. Moreover, miR-16-5p was testified to target IRS1. IRS1 silencing alleviated miR-16-5p knockdown-mediated inhibition of apoptosis in AC16 cells. Conclusion: miR-16-5p knockdown increased cell viability and angiogenesis, as well as inhibited cell apoptosis by increasing IRS1. These findings indicated that miR-16-5p knockdown may be a new therapeutic target for myocardial infarction.

AAnti-Inflammatory Effects of Plasma Circulating Exosomes Obtained from Normal-Weight and Obese Subjects on Hepatocytes

2020 ◽  
Vol 20 ◽  
Author(s):  
Reza Afrisham ◽  
Sahar Sadegh-Nejadi ◽  
Reza Meshkani ◽  
Solaleh Emamgholipour ◽  
Molood Bagherieh ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Hepg2 Cells ◽  
Human Liver ◽  
Liver Cells ◽  
Normal Weight ◽  
Protein Levels ◽  
Human Liver Cells ◽  
Tnf Α ◽  
Anti Inflammatory

Introduction: Obesity is a disorder with low-grade chronic inflammation that plays a key role in the hepatic inflammation and steatosis. Moreover, there are studies to support the role of exosomes in the cellular communications, the regulation of metabolic homeostasis and immunomodulatory activity. Accordingly, we aimed to evaluate the influence of plasma circulating exosomes derived from females with normal-weight and obesity on the secretion of inflammatory cytokines in human liver cells. Methods: Plasma circulating exosomes were isolated from four normal (N-Exo) and four obese (O-Exo) women. The exosomes were characterized and approved for CD63 expression (common exosomal protein marker) and morphology/size using the western blot and TEM methods, respectively. The exosomes were used for stimulation of HepG2 cells in vitro. After 24 h incubation, the protein levels of TNF-α,IL-6, and IL-1β were measured in the culture supernatant of HepG2 cells using the ELISA kit. Results: The protein levels of IL-6 and TNF-α in the cells treated with O-Exo and N-Exo reduced significantly in comparison with control group (P=0.039 and P<0.001 respectively), while significance differences were not found between normal and obese groups (P=0.808, and P=0.978 respectively). However, no significant differences were found between three groups in term of IL-1β levels (P=0.069). Based on the correlation analysis, the protein levels of IL-6 were positively correlated with TNF-α (r 0.978, P<0.001). Conclusion: These findings suggest that plasma circulating exosomes have probably anti-inflammatory properties independently from body mass index and may decrease the secretion of inflammatory cytokines in liver. However, further investigations in vitro and in vivo are needed to address the anti-inflammatory function of N-Exo and O-Exo in human liver cells and/or other cells.

scholarly journals Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial

Open Heart ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. e001614
Author(s):  
Mohammad R Ostovaneh ◽  
Raj R Makkar ◽  
Bharath Ambale-Venkatesh ◽  
Deborah Ascheim ◽  
Tarun Chakravarty ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Clinical Trial ◽  
Myocardial Function ◽  
Randomised Clinical Trial ◽  
Scar Tissue ◽  
Left Ventricular ◽  
Lv Function ◽  
Cardiac Events ◽  
Lv Dysfunction ◽  
Registration Number

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups.ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

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