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Biomedical subjects

Ilka Ott

Publications and source records attributed to Ilka Ott.

13 recordsLinked to original sources
PubMed2006

Cytokine profiles and T cell function in acute coronary syndromes.

AIMS: In advanced human atherosclerotic plaques infiltrating T cells congregate at sites of plaque rupture. However, little is known about the systemic activation of circulating T cells in acute coronary syndromes as a prerequisite for recruitment to atherosclerotic lesions. METHODS AND RESULTS: As a measure for specific lymphocyte activation we analyzed IFN-gamma production of T cells after stimulation with a superantigen and expression of CXCR-3 and CCR-3 in patients with acute myocardial infarction (AMI), unstable angina (uAP) or stable angina (sAP). Furthermore, concentrations of the circulating cytokines interleukin (IL)-1, IL-6, IL-1beta, IL-12 p70 and RANTES that modify T cell function were measured. In uAP an increased Th1 and a decreased Th2 response was identified by enhanced interferon-gamma generation of T lymphocytes, increased levels of IL-1beta, IL-12 p70 and RANTES and decreased expression of CCR3. In AMI a systemic inflammatory reaction predominates with enhanced expression of the early activation marker CD69 on T lymphocytes and elevated levels of IL-6 and IL-10 that suppress Th1 activation. CONCLUSION: Interferon-gamma production of activated T cells in acute coronary syndromes may, therefore, be governed by the release of specific pro- and anti-lymphocyte activating cytokines.

Acute Disease↗
PubMed2006

Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial.

CONTEXT: Experimental studies and early phase clinical trials suggest that transplantation of blood-derived or bone marrow-derived stem cells may improve cardiac regeneration and neovascularization after acute myocardial infarction. Granulocyte colony-stimulating factor (G-CSF) induces mobilization of bone marrow stem cells. OBJECTIVE: To assess the value of stem cell mobilization by G-CSF therapy in patients with acute myocardial infarction. DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, placebo-controlled trial of patients diagnosed with ST-segment elevation acute myocardial infarction who had successful reperfusion by percutaneous coronary intervention within 12 hours after onset of symptoms in Germany between February 24, 2004, and February 2, 2005. INTERVENTIONS: Patients were randomly assigned to receive subcutaneously either a daily dose of 10 microg/kg of G-CSF or placebo for 5 days. MAIN OUTCOME MEASURES: The primary end point was reduction of left ventricular infarct size according to technetium Tc 99m sestamibi scintigraphy performed at baseline and at 4 to 6 months after randomization. Secondary end points included improvement of left ventricular ejection fraction measured by magnetic resonance imaging and the incidence of angiographic restenosis. RESULTS: Of the 114 patients, 56 were assigned to receive treatment with G-CSF and 58 were assigned to receive placebo. Treatment with G-CSF produced a significant mobilization of stem cells. Between baseline and follow-up, left ventricular infarct size according to scintigraphy was reduced by a mean (SD) of 6.2% (9.1%) in the G-CSF group and 4.9% (8.9%) in the placebo group (P = .56) and left ventricular ejection fraction was improved by 0.5% (3.8%) in the G-CSF group and 2.0% (4.9%) in the placebo group (P = .14). Angiographic restenosis occurred in 19 (35.2%) of 54 patients in the G-CSF group and in 17 (30.9%) of 55 patients in the placebo group (P = .79). The most common adverse event among patients assigned to G-CSF was mild to moderate bone pain and muscle discomfort. CONCLUSION: Stem cell mobilization by G-CSF therapy in patients with acute myocardial infarction and successful mechanical reperfusion has no influence on infarct size, left ventricular function, or coronary restenosis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00126100.

Aged↗
PubMed2006

Interleukin-8 is associated with circulating CD133+ progenitor cells in acute myocardial infarction.

AIMS: Release of progenitor cells is observed during inflammatory conditions and contributes to neovascularization. We, therefore, sought to investigate the relationship of circulating progenitor cells and interleukin (IL)-8 in acute myocardial infarction (AMI). METHODS AND RESULTS: From patients with stable angina and AMI, serial venous blood samples were obtained. The number of circulating CD133+CD45- progenitor cells, endothelial progenitor cells (EPCs), and circulating endothelial P1H12+CD45- cells was analyzed by flow cytometry. After stenting in patients with AMI, an increase in plasma IL-8 and vascular endothelial growth factor (VEGF) concentrations was observed, which was only minimal in patients with stable angina. Only in patients with AMI, this was followed by an increase in circulating CD133+CD45- progenitor cells. In contrast, circulating endothelial P1H12+CD45- cells and E-selectin RNA expression in peripheral blood were only elevated early in AMI, indicating shedding of activated endothelial cells. Multivariable analysis revealed an association of IL-8 and circulating CD133+CD45- progenitor cells in AMI, in addition to statin therapy and risk factor profile. CONCLUSION: In AMI, IL-8 is associated with circulating progenitor cells. In addition to the pro-angiogenic functions of IL-8 and VEGF, this mechanism may contribute to new vessel generation and, thereby, improve myocardial function.

AC133 Antigen↗
PubMed2005

Vascular remodeling in mice lacking the cytoplasmic domain of tissue factor.

Tissue factor (TF), the cell surface receptor for the serine protease FVIIa supports cell migration by interaction with the cytoskeleton. Intracellular signaling pathways dependent on the cytoplasmic domain of TF modify cell migration and may alter vascular remodeling. Vascular remodeling was analyzed in a femoral artery injury and a blood flow cessation model in mice with a targeted deletion of the 18 carboxy-terminal intracellular amino acids of TF (TF(Deltact/Deltact)) and compared with TF wild-type mice (TF(wt/wt)). Morphometric analysis revealed a decrease in the intima/media ratio after vascular injury in arteries from TF(Deltact/Deltact) compared with TF(wt/wt) mice (femoral artery injury: 2.4+/-0.3 TF(wt/wt) versus 0.6+/-0.3 TF(Deltact/Deltact), n=9 to 10, P=0.002; carotis ligation: 0.45+0.11 TF(wt/wt) versus 0.22+0.03 TF(Deltact/Deltact), n=12 to 14, P=0.09). This was caused by an increase in the media by 54% (P=0.04) in the femoral artery model and by 32% (P=0.03) after carotis ligation and was associated with an increased number of proliferating cells. Isolated aortic smooth muscle cells (SMCs) of TF(wt/wt) mice showed an increased migratory response toward the TF ligand active site-inhibited FVIIa that was abolished in TF(Deltact/Deltact) SMC. In contrast, the unstimulated proliferation rate was increased in TF(Deltact/Deltact) SMC compared with TF(wt/wt) SMCs. Thus, retention of SMCs attributable to a migratory defect and increased proliferation results in thickening of the media and in decrease in neointima formation after arterial injury. TF cytoplasmic domain signaling alters vascular remodeling and, thereby, may play a role in the development of restenosis, atherosclerotic disease, and neovascularization.

Animals↗
PubMed2005

Endothelial-like cells expanded from CD34+ blood cells improve left ventricular function after experimental myocardial infarction.

Mobilization and recruitment of endothelial progenitor cells (EPC) contributes to vasculogenesis in vivo. So far, applications for cell therapy are limited by the number of available cells. Expansion of EPC or their progeny may, therefore, facilitate its therapeutic use in ischemic disease. The aim of this study was to expand CD34+ EPC-derived progeny from different sources, characterize them, and investigate their potential for use in therapeutic vasculogenesis. CD34+ cells from G-CSF-mobilized peripheral blood (PB) and cord blood (CB) were isolated using immunomagnetic beads and cultured in endothelial cell medium. Cells were expanded up to 16 (PB) and up to 46 (CB) population doublings, respectively. Immunophenotypic and mRNA expression analyses showed a high degree of similarity between the cultured cells and human umbilical vein endothelial cells (HUVEC). By day 14 after transplantation, transplanted human CD31-positive EPC-derived cells were detected. These cells expressed the proliferation marker Ki67 and formed vessel-like structures in ischemic myocardium. Most strikingly, transplantation of EPC-derived cells improved left ventricular function after experimental ischemia, as shown by echocardiography. In conclusion, cells cultured from CD34+ EPC can be expanded in vitro to clinically relevant numbers. In vivo, these cells proliferate, form vascular structures, and improve left ventricular function after experimental myocardial infarction. Therefore, in vitro expanded EPC-derived endothelial cells may be beneficial in the treatment of ischemic disease.

Animals↗
PubMed2005

Tissue factor cytoplasmic domain stimulates migration by activation of the GTPase Rac1 and the mitogen-activated protein kinase p38.

BACKGROUND: Tissue factor (TF), the surface receptor for the serine protease factor VIIa (FVIIa) and the initiator of the extrinsic coagulation cascade, supports vessel development and tumor metastasis by activation of extracellular, protease-dependent signaling pathways. The molecular mechanisms that do not require proteolytic activity of FVIIa are not yet known. The aim of the study, therefore, was to investigate the effects of active-site-inhibited FVIIa (FFR-FVIIa) on TF-mediated signaling. METHODS AND RESULTS: After stimulation with FVIIa and FFR-FVIIa, migration and activation of the GTPase Rac (Rac1) or the mitogen-activated protein kinase p38 (p38) were analyzed in J82 cells. FVIIa and FFR-FVIIa stimulated migration and activation of Rac1 and p38 in a TF-specific, dose- and time-dependent manner. Enhancement of migration required activation of Rac1 and p38, because it was abolished after inhibition with SB203580 or overexpression of dominant negative p38 and Rac1. The cytoplasmic domain of TF was necessary because no effects of FFR-FVIIa could be detected after transfection of a TF deletion mutant lacking the cytoplasmic domain. CONCLUSIONS: We identified a novel signaling pathway through which TF stimulates migration by activation of p38 and Rac1 independent of the proteolytic activity of FVIIa but dependent on the cytoplasmic domain of TF. Binding of FFR-VIIa to TF may stimulate vessel wall remodeling by enhancement of migration through activation of Rac1 and p38. This novel link may provide an insight into the understanding of the nonhemostatic functions of TF.

Cell Line, Tumor↗
PubMed2005

Tissue factor pathway inhibitor on circulating microparticles in acute myocardial infarction.

In acute myocardial infarction (AMI), increased Tissue Factor (TF) expression on circulating monocytes and microparticles (MP) may contribute to thrombotic events. Because surfacebound Tissue Factor Pathway Inhibitor-1 (TFPI) inhibits TF activity on monocytes and endothelial cells decreased TFPI expression may reinforce the procoagulant activity of circulating MP. Aim of the study was to analyze TFPI expression and TF activity after stenting and thrombolysis inAMI. Thirty-nine patients of a randomized study comparing intravenous thrombolysis (n=19) and stenting (n=20) were included. Before and after therapy blood samples for analysis of MPs, TF antigen and activity, prothrombin fragment F1+2 and D-dimer were obtained. TFPI expression on TF positive MPs was decreased after thrombolysis but not after stenting. In contrast, TF plasma levels and TF positive MP remained unchanged in both treatment groups. After thrombolysis increased D-dimer and F1+2 plasma concentrations indicated activation of fibrinolysis and coagulation. Significance of MPTFPI for inhibition of TF activity was measured using inhibitory TFPI antibodies. Membrane-associated TFPI inhibited TF activity on circulating MPs. After thrombolysis inhibition of TF activity by TFPI was decreased as compared to stenting. Correlation of circulating TF with F1+2 only after thrombolysis, suggests a role for TF-induced activation of coagulation after thrombolysis. Enhanced TF activity on circulating MPs in AMI is inhibited by endogenous surface-boundTFPI. After thrombolysis but not after stenting MPTFPI is degraded and may induce thrombin generation due to unopposed tissue factor activity. Anti-TF therapies during thrombolysis may reduce thrombin generation in AMI.

Aged↗
PubMed2004

Coagulation factor Xa stimulates interleukin-8 release in endothelial cells and mononuclear leukocytes: implications in acute myocardial infarction.

OBJECTIVE: In acute myocardial infarction (AMI), proinflammatory plasma C-reactive protein values are strongly associated with postinfarction morbidity and mortality. So far, the cause of these inflammatory changes is not well understood. Therefore, we sought to investigate the relationship between the activation of coagulation and subsequent systemic inflammatory changes in AMI. METHODS AND RESULTS: Factor Xa (FXa) bound to tissue factor pathway inhibitor and prothrombin fragments F1+2 (F1+2) were used as a measure for activated coagulation. To assess systemic inflammatory changes, plasma interleukin (IL)-6 and IL-8 concentrations were analyzed by immunoassay. Blood samples were taken from 21 patients with AMI and 20 patients with stable angina pectoris. In AMI, tissue factor pathway inhibitor FXa but not F1+2 plasma levels were associated with circulating IL-8 (P=0.01). In vitro experiments revealed that FXa stimulated IL-8 and monocyte chemoattractant protein-1 release and RNA expression in endothelial cells and mononuclear leukocytes by activation of protease-activated receptor-1. CONCLUSIONS: Our data suggest that coagulation FXa may contribute to proinflammatory changes in AMI by stimulation of IL-8 release. Therapeutic inhibition of the proinflammatory effects of FXa may improve the clinical course in AMI. This study investigates the relationship between the activation of coagulation and systemic inflammatory changes in acute myocardial infarction. Tissue factor pathway inhibitor factor Xa but not F1+2 plasma levels were associated with circulating interleukin-8. In vitro factor Xa stimulated interleukin-8 and monocyte chemoattractant protein-1 release and RNA expression by activation of protease-activated receptor 1 as an underlying mechanism.

Adult↗
PubMed2004

Tissue factor promotor polymorphism -603 A/G is associated with myocardial infarction.

Tissue factor (TF), the main initiator of the extrinsic coagulation cascade is expressed in atherosclerotic lesions and contributes to coronary thrombus formation in myocardial infarction (MI). Circulating TF reflects intravascular TF activation but also adds to prothrombotic activation. Because the G allele of the TF promotor polymorphism -603 A/G is associated with monocytic mRNA expression we evaluated its association with myocardial infarction, based on a recessive deleterious effect assumption. Patients with MI (MI; n=793) and age and sex matched control subjects without coronary artery disease (C; n=340) undergoing coronary angiography were included. In patients with MI, the -603 G (MI: 76%, C: 70%) allele was prevalent compared to the control group (P=-0.04). Multivariate analysis revealed an odds ratio of 1.44 (confidence interval 1.07-1.93). Carriage of the -603 G allele is associated with an increased risk for myocardial infarction. Because higher plasma TF concentrations are found in -603 G carriers enhanced TF expression may be the mechanism underlying this association.

Adenine↗
PubMed2003

Tissue factor in acute coronary syndromes.

Thrombosis at the site of atherosclerotic plaque disruption is the principal cause of acute coronary syndromes. The severity of the clinical consequences is determined by the extent and the progression of the thrombus that are caused by local and systemic factors. In atherosclerotic lesions mediators induce tissue factor (TF) in macrophages, smooth muscle cells, and endothelial cells. Procoagulant microparticles in the lipid core further enhance the thrombogenicity of the plaque. In addition, in acute coronary syndromes circulating monocytes and microparticles express TF and, thereby, contribute to systemic procoagulant activity. As a regulatory mechanism surface-bound, endogenous tissue factor pathway inhibitor-1 (TFPI) inhibits TF activity by translocation of the quaternary complex TF-FVIIa-FXa-TFPI into glycosphingolipid-rich microdomains more efficiently than exogenously added TFPI. This inhibition occurs not only in endothelial cells but also on circulating monocytes and presumably microparticles. Because therapeutic thrombolysis in acute myocardial infarction degrades TFPI, a prothrombotic state due to unopposed TF activity may occur. Several studies have demonstrated a contribution of local and bloodborne TF to thrombus formation; a direct relationship with the clinical outcome, however, awaits further studies. This article discusses the current understanding of the role of TF and its regulation by TFPI in acute coronary syndromes.

Angina, Unstable↗
PubMed2003

Overexpression of glycosyl phosphatidylinositol-anchored tissue factor pathway inhibitor-1 inhibits tissue factor activity.

The cellular initiation of coagulation by the tissue factor (TF)-activated factor VII complex is transiently inhibited by endogenous tissue factor pathway inhibitor-1 (TFPI-1), whereas exogenously added TFPI-1 is targeted to a degradation pathway. This study investigates the relevance of glycosyl phosphatidylinositol (GPI) anchoring for the anticoagulant properties of TFPI-1. Experiments were performed with the human cell line ECV304 using liposomal gene transfer. For GPI anchoring of TFPI-1 we used a fusion protein of TFPI-1 and the GPI attachment sequence of decay-accelerating factor (GPI-TFPI-1), and compared it with wild-type TFPI-1. We measured TF and TFPI-1 surface expression by flow cytometry and TF proteolytic activity by a chromogenic assay for activated factor X generation. After transfection of GPI-TFPI-1, surface expression of TFPI-1 increased to 134 +/- 9% of mock transfected cells (mean +/- SEM, P = 0.004), and transfection with wild-type TFPI-1 did not significantly alter TFPI-1 surface expression. After transfection with GPI-TFPI-1, TF activity was reduced by 18 +/- 9% compared with mock transfections (P = 0.003), whereas after transfection with TFPI-1 wild type no significant inhibition was observed. This effect was not due to altered TF expression. GPI anchoring is an essential prerequisite for surface expression of TFPI-1 and inhibition of TF activity. Gene transfer of GPI-anchored TFPI, therefore, may be an efficient tool to inhibit local TF-induced coagulation.

Anticoagulants↗
PubMed2002

Proteolysis of tissue factor pathway inhibitor-1 by thrombolysis in acute myocardial infarction.

BACKGROUND: In acute myocardial infarction (AMI), surface-bound tissue factor pathway inhibitor-1 (TFPI-1) inhibits an increased monocyte procoagulant activity. In addition, TFPI-1 is released from microvascular endothelial cells after treatment with heparin and thereby contributes to its antithrombotic properties. METHODS AND RESULTS: We examined 19 patients in a randomized study comparing intravenous fibrinolysis with alteplase (n=9) and revascularization by stent placement with additional abciximab treatment (n=10). We obtained blood samples for analysis of monocytic TFPI-1 surface expression by flow cytometry and plasma TFPI-1 concentrations by immunoassay before and after therapy. We found a significant decrease in surface TFPI-1 on circulating monocytes 24 hours after thrombolysis (P=0.006) that was not observed after stenting. Systemic plasma TFPI-1 concentrations increased immediately after stenting by 71+/-14% (P=0.008), whereas after thrombolysis, a decrease in TFPI-1 plasma concentrations of 21+/-11% was observed (P=0.075). In vitro experiments confirmed that plasmin decreased TFPI-1 surface expression dose-dependently. CONCLUSIONS: Activation of the fibrinolytic system by alteplase in AMI decreases surface-associated TFPI-1 on circulating monocytes and plasma TFPI-1. Reduced TFPI-1 may contribute to thrombotic complications after fibrinolysis in AMI.

Abciximab↗