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Harald Langer

Publications and source records attributed to Harald Langer.

13 recordsLinked to original sources
PubMed2006

Platelets induce differentiation of human CD34+ progenitor cells into foam cells and endothelial cells.

Recruitment of human CD34+ progenitor cells toward vascular lesions and differentiation into vascular cells has been regarded as a critical initial step in atherosclerosis. Previously we found that adherent platelets represent potential mediators of progenitor cell homing besides their role in thrombus formation. On the other hand, foam cell formation represents a key process in atherosclerotic plaque formation. To investigate whether platelets are involved in progenitor cell recruitment and differentiation into endothelial cells and foam cells, we examined the interactions of platelets and CD34+ progenitor cells. Cocultivation experiments showed that human platelets recruit CD34+ progenitor cells via the specific adhesion receptors P-selectin/PSGL-1 and beta1- and beta2-integrins. Furthermore, platelets were found to induce differentiation of CD34+ progenitor cells into mature foam cells and endothelial cells. Platelet-induced foam cell generation could be prevented partially by HMG coenzyme A reductase inhibitors via reduction of matrix metalloproteinase-9 (MMP-9) secretion. Finally, agonists of peroxisome proliferator-activated receptor-alpha and -gamma attenuated platelet-induced foam cell generation and production of MMP-9. The present study describes a potentially important mechanism of platelet-induced foam cell formation and generation of endothelium in atherogenesis and atheroprogression. The understanding and modulation of these mechanisms may offer new treatment strategies for patients at high risk for atherosclerotic diseases.

Antigens, CD34↗
PubMed2006

Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation.

AIMS: To assess whether low response to clopidogrel influences cardiovascular outcome after coronary stent implantation in a consecutively measured cohort of patients with coronary stent implantation. METHODS AND RESULTS: A total of 379 consecutive patients with symptomatic coronary artery disease (CAD), (stable angina n = 206 and acute coronary syndrome, n = 173) treated with percutaneous coronary stenting were enrolled in this trial. Responsiveness to clopidogrel was assessed by ADP (20 micromol/L)-induced aggregometry at least 6 h (mean 34.8+/-25.9 h) after administration of a loading dose of 600 mg clopidogrel. Platelet inhibition < 30% was defined as low response to clopidogrel. At 3-month follow-up, the primary outcome of a combined major cardiovascular event including non-fatal myocardial infarction, non-fatal ischaemic stroke, or cardiovascular death was evaluated. Twenty-two patients (5.8%) were classified as low responders. Compared with patients who adequately responded to clopidogrel, a low responder had a significantly higher risk of major cardiovascular events [22.7 vs. 5.6%; odds ratio, 4.9; 95% confidence interval (CI), 1.66-14.96; P = 0.004]. After adjustment for other factors influencing cardiovascular outcome, low response to clopidogrel and severe left ventricular dysfunction were independently associated with a major cardiovascular event within 3 months (hazard ratio for low response to clopidogrel, 3.71; 95% CI, 1.08-12.69; P = 0.037). CONCLUSION: Low response to clopidogrel in patients with symptomatic CAD treated by stenting significantly enhances the occurrence of cardiovascular events and death. The evaluation of low response to clopidogrel may help to identify patients at increased risk who may benefit from intensified antiplatelet strategy.

Adult↗
PubMed2006

Expression of platelet collagen receptor glycoprotein VI is associated with acute coronary syndrome.

AIMS: Platelet collagen receptor glycoprotein VI (GPVI) is critical for the formation of arterial thrombosis. In this observational study, we examined the platelet surface expression of GPVI in patients with symptomatic coronary artery disease (CAD). METHODS AND RESULTS: We evaluated a consecutive cohort of 367 patients with symptomatic CAD, who underwent coronary angiography. The surface expression of platelet activation markers (GPVI, CD62P, and CD42b) was determined by flow cytometry. Patients with acute coronary syndrome (ACS) showed a significantly enhanced GPVI expression on admission when compared with patients with stable angina pectoris (SAP) (ACS: 21.4+/-9.7; SAP: 18.6+/-7.1 mean fluorescence intensity+/-SD; P=0.004). The expression of GPVI correlated with CD62P (r=0.702; P=0.001). Logistic regression analysis demonstrated that on admission, elevated platelet GPVI expression was associated with ACS, independent of markers of myocardial necrosis such as troponin and creatine kinase. CONCLUSION: Platelet GPVI surface expression is elevated in patients with ACS and is associated with imminent acute coronary events. The determination of the platelet-specific thrombotic marker GPVI may help to identify patients at risk before myocardial ischaemia is evident.

Adult↗
PubMed2006

[Role of platelets in atherosclerosis and inflammation].

BACKGROUND: Platelets are an important link between inflammation, thrombosis, and atherogenesis. Inflammation is characterized by interactions among platelets, leukocytes, and endothelial cells. These interactions trigger autocrine and paracrine activation processes that lead to leukocyte recruitment into the vascular wall. Platelet-induced chronic inflammatory processes at the vascular wall result in development of atherosclerotic lesions and atherothrombosis. METHODS: In vitro studies with co-incubated human endothelial cells and platelets after physical denudation or activation of the endothelium by cytokines provided important results for the understanding of adhesion mechanisms and the involvement of different adhesion receptors, like integrins and selectins. Furthermore, in in vivo mouse models platelet-endothelium interactions under dynamic flow conditions and increased shear stress could be analyzed. With the help of intravital microscopy, the availability of appropriate atherosclerotic animal models and first conclusive data obtained in humans, the important role of platelets in atheroprogression could be confirmed in vivo. CONCLUSION: This review highlights the molecular machinery and inflammatory pathways used by platelets to initiate and accelerate atherothrombosis. Understanding the specific requirements for platelets adhering to endothelium may lead to the development of novel therapeutic strategies.

Animals↗
PubMed2006

Platelets secrete stromal cell-derived factor 1alpha and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo.

The accumulation of smooth muscle and endothelial cells is essential for remodeling and repair of injured blood vessel walls. Bone marrow-derived progenitor cells have been implicated in vascular repair and remodeling; however, the mechanisms underlying their recruitment to the site of injury remain elusive. Here, using real-time in vivo fluorescence microscopy, we show that platelets provide the critical signal that recruits CD34+ bone marrow cells and c-Kit+ Sca-1+ Lin- bone marrow-derived progenitor cells to sites of vascular injury. Correspondingly, specific inhibition of platelet adhesion virtually abrogated the accumulation of both CD34+ and c-Kit+ Sca-1+ Lin- bone marrow-derived progenitor cells at sites of endothelial disruption. Binding of bone marrow cells to platelets involves both P-selectin and GPIIb integrin on platelets. Unexpectedly, we found that activated platelets secrete the chemokine SDF-1alpha, thereby supporting further primary adhesion and migration of progenitor cells. These findings establish the platelet as a major player in the initiation of vascular remodeling, a process of fundamental importance for vascular repair and pathological remodeling after vascular injury.

Animals↗
PubMed2006

Local delivery of soluble platelet collagen receptor glycoprotein VI inhibits thrombus formation in vivo.

Platelet-mediated thrombus formation at the site of vascular injury is a major trigger for thrombo-ischemic complications after coronary interventions. The platelet collagen receptor glycoprotein VI (GPVI) plays a critical role in the initiation of arterial thrombus formation. Endothelial denudation of the right carotid artery in rabbits was induced through balloon injury. Subsequently, local delivery of soluble, dimeric fusion protein of GPVI (GPVI-Fc) (n = 7) or control Fc (n = 7) at the site of vascular injury was performed with a modified double-balloon drug-delivery catheter. Thrombus area within the injured carotid artery was quantified using a computer-assisted image analysis and was used as index of thrombus formation. The extent of thrombus formation was significantly reduced in GPVI-Fc- compared with control Fc-treated carotid arteries (relative thrombus area, GPVI-Fc vs. Fc: 9.3 +/- 4.2 vs. 2.3 +/- 1.7, p < 0.001). Local delivery of soluble GPVI resulted in reduced thrombus formation after catheter-induced vascular injury. These data suggest a selective pharmacological modulation of GPVI-collagen interactions to be important for controlling onset and progression of pathological arterial thrombosis, predominantly or even exclusively at sites of injured carotid arteries in the absence of systemic platelet therapy.

Animals↗
PubMed2005

Adherent platelets recruit and induce differentiation of murine embryonic endothelial progenitor cells to mature endothelial cells in vitro.

The homing and differentiation mechanisms of endothelial progenitor cells (EPCs) at sites of vascular lesions are unclear. To investigate whether platelets play a role in the recruitment and differentiation of EPCs, we made use of a robust mouse embryonic EPC (eEPC) line that reliably differentiates to a mature endothelial phenotype. We found that platelets stimulate chemotaxis and migration of these murine eEPCs. Further, the substantial adhesion of murine eEPCs on immobilized platelets that occurs under dynamic flow conditions is inhibited by neutralizing anti-P-selectin glycoprotein ligand-1 and anti-VLA-4 (beta1-integrin) monoclonal antibodies but not by anti-CD11b (aM-integrin; macrophage antigen-1). Coincubation of murine eEPCs with platelets for 5 days induced differentiation of EPCs to mature endothelial cells as verified by positive von Willebrand factor immunofluorescence and detection of Weibel Palade bodies through electron microscopy. We conclude that platelets may play a critical part in the capture and subsequent differentiation of murine eEPCs at sites of vascular lesions, revealing a possible new role of platelets in neoendothelization after vascular injury.

Animals↗
PubMed2005

[The coagulation cascade--clinical implications].

The coagulation system is a cascade of complex, interacting steps, that can selectively be inhibited in distinct ways. Thus, various therapeutic options are offered, concerning primary hemostasis, which results in formation of a platelet-rich thrombus, as well as secondary hemostasis, resulting in fibrin formation. For patients with coronary artery disease, who have to undergo percutaneous coronary intervention (PCI), a sufficient anticoagulant strategy is essential for prevention of ischemic events, due to the activated state of the coagulation system of these patients. Next to antiplatelet therapy, unfractionated heparin (UFH) is a well-established concomitant intravenous therapy during PCI. Also low-molecular-weight heparins (LMWH) are increasingly used in this setting due to their favorable pharmacodynamic properties. The exact value of these substances in comparison to UFH is not completely evaluated yet.

Anticoagulants↗
PubMed2005

ADAM 15 is an adhesion receptor for platelet GPIIb-IIIa and induces platelet activation.

Cell adhesion and proteolytic matrix degradation are central processes in atherosclerosis. Being a member of the family of ADAMs ("a disintegrin and metalloproteinase"), metargidin (ADAM15) combines a metalloproteinase domain and an RGD aminoacid sequence. We studied the potential role of ADAM15 as an adhesion receptor on endothelial cells and interactions between platelets and ADAM15 with respect to platelet adhesion, activation and thrombus formation. ADAM15 was found to be expressed on cultured endothelial cells (HUVEC). Platelet adhesion to immobilized recombinant ADAM15 was effectively enhanced under both static and high shear rate conditions reaching the maximum level of adhesion to fibrinogen. Consistently, platelet adhesion onto ADAM15 overexpressing endothelial cells was significantly increased. Adhesion to ADAM15 was reduced by blockade of GPIIb-IIIa using neutralizing anti-alpha(IIb)beta3 mAbs (7E3, 2G12), but not by anti-alpha(v)beta3 (LM609). Soluble ADAM15 binds to activated but not to resting GPIIb-IIIa. Moreover, platelets adherent to ADAM15 additionally attracted platelets under high shear rates indicating an initial role of platelet-ADAM15 interactions for thrombus formation. Furthermore, incubation of platelets with soluble ADAM15 showed a dose-dependent increase in secretion of CD62P and CD40L. ADAM15 is expressed on endothelial cells and can serve as an adhesion receptor for platelets via GPIIb-IIIa binding. Platelet adhesion to ADAM15 leads to platelet activation, secretion and promotes thrombus formation. Thus, ADAM15 may represent a novel target for antithrombotic strategies in cardiovascular pathologies.

ADAM Proteins↗
PubMed2005

Platelets in inflammation and atherogenesis.

Platelets represent an important linkage between inflammation, thrombosis, and atherogenesis. Inflammation is characterized by interactions among platelets, leukocytes, and ECs. These interactions trigger autocrine and paracrine activation processes that lead to leukocyte recruitment into the vascular wall. Platelet-induced chronic inflammatory processes at the vascular wall result in development of atherosclerotic lesions and atherothrombosis. This Review highlights the molecular machinery and inflammatory pathways used by platelets to initiate and accelerate atherothrombosis.

Animals↗
PubMed2003

Soluble glycoprotein VI dimer inhibits platelet adhesion and aggregation to the injured vessel wall in vivo.

Platelet-collagen interactions play a fundamental role in the process of arterial thrombosis. The major platelet collagen receptor is the glycoprotein VI (GPVI). Here, we determined the effects of a soluble dimeric form of GPVI on platelet adhesion in vitro and in vivo. We fused the extracellular domain of GPVI with the human immunoglobulin Fc domain. The soluble dimeric form of GPVI (GPVI-Fc) specifically bound to immobilized collagen. Binding of GPVI-Fc to collagen was inhibited competitively by soluble GPVI-Fc, but not control Fc lacking the external GPVI domain. GPVI-Fc inhibited the adhesion of CHO cells that stably express human GPVI and of platelets on collagen and attenuated thrombus formation under shear conditions in vitro. To test the effects of GPVI-Fc in vivo, arterial thrombosis was induced in the mouse carotid artery, and platelet-vessel wall interactions were visualized by intravital fluorescence microscopy. Infusion of GPVI-Fc but not of control Fc virtually abolished stable arrest and aggregation of platelets following vascular injury. Importantly, GPVI-Fc but not control Fc, was detected at areas of vascular injury. These findings further substantiate the critical role of the collagen receptor GPVI in the initiation of thrombus formation at sites of vascular injury and identify soluble GPVI as a promising antithrombotic strategy.

Animals↗
PubMed2003

Low-molecular-weight heparin (reviparin) diminishes tumor cell adhesion and invasion in vitro, and decreases intraperitoneal growth of colonadeno-carcinoma cells in rats after laparoscopy.

BACKGROUND: Metastases, adhesion and invasion of tumor cells involve a cascade of complex phenomena, which potentially can be affected by glycosaminoglycans. We studied the influence of a low-molecular-weight heparin, reviparin, on the intraabdominal tumor growth in rats undergoing laparoscopy. We also studied cytotoxicity, anti-adhesive, and anti-invasive effects of reviparin in vitro using adenocarcinoma cells CC531. METHODS: In vitro assays: Adhesion of 1 x 10(5) CC531 adenocarcinoma cells onto microtiter plates coated with 10 microg/ml collagen type I or 10 microg/ml Matrigel was studied in the presence of 0.55; 1.10 and 2.76 mg/ml reviparin, and compared to saline. The cytotoxicity of 1 x 10(4) adenocarcinoma cells was studied in a similar assay. Transwell dual chambers with polycarbonate filters coated with 100 microg/cm2 Matrigel were used to investigate the effect of 0.55; 1.10 and 2.76 mg/ml reviparin on the invasion of 1 x 10(5) adenocarcinoma cells/ml. In vivo experiments: CC531 adenocarcinoma cells (5 x 10(6) cells/ml) were intraperitoneally applied to Wistar Albino Glaxo rats (n=150, Harlan, Germany) with a median weight of 278 g. The rats were divided into 15 groups with 10 animals in each group, underwent laparoscopy, and 1 ml saline containing 0, 0.5, 2.0, 4.0, and 10 mg reviparin per kg b.w. was introduced for intraperitoneal lavage or s.c. After 21 days the animals underwent an autopsy, and the tumor weight was determined. RESULTS: In vitro experiments: We found a highly significant inhibition of tumor cell adhesion and invasion (p<0.001) by all reviparin concentrations used in the assays. There was no effect of reviparin on the viability of cells in the cytoxicity assay. In vivo experiments: We found that application of 4.0 and 10.0 mg/kg b.w., but not 0.5 or 2.0 mg/kg b.w. significantly (p<0.01) decreased the tumor mass compared to controls, receiving only saline. This effect was most pronounced after the combined i.p. and s.c. application, whereas after a sole i.p. application, only the highest dose of 10 mg/kg b.w. caused a significant inhibition of tumor growth. CONCLUSION: Low-molecular-weight heparin, reviparin, given in combination of i.p. lavage and s.c. injections, significantly diminishes intraabdominal tumor growth of CC531 adenocarcinoma cells in rats undergoing laparoscopy. This may offer additional therapeutic options for patients undergoing laparoscopic cancer surgery.

Abdominal Neoplasms↗