Harald Langer

University of Tuebingen, Tübingen, Baden-Württemberg, Germany

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Publications (101)679.28 Total impact

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    ABSTRACT: Recently, we reported that extracellular cyclophilin A (CyPA) is an important agonist for platelets. Whereas soluble CyPA-levels have been associated with cardiovascular risk factors, cell-bound CyPA has not been investigated yet. In this study, we analyzed for the first time platelet-bound CyPA in patients with symptomatic coronary artery disease (CAD). blood was obtained from 388 consecutive patients: 204 with stable CAD and 184 with acute coronary syndrome (76 with unstable angina, 78 with non ST-elevation myocardial infarction (NSTEMI), and 30 with STEMI). In vitro stimulation of platelets with classical agonists revealed an enhanced expression of CyPA on the platelet surface. In patients with stable CAD, platelet-bound CyPA correlated excellently with platelet activity measured by P-selectin exposure in flow cytometry. The analysis of classical risk factors for atherosclerosis revealed that patients with hypertension and hypercholesterolemia had significantly enhanced platelet-bound CyPA, whereas diabetes and smoking were not associated with enhanced CyPA-binding to the platelet surface. In multivariate analysis, hypercholesterolemia was the only significant predictor of enhanced platelet-bound CyPA. Interestingly, in patients with acute myocardial infarction (AMI) platelet-bound CyPA was significantly decreased compared with patients with stable CAD. Enhanced platelet-bound CyPA is associated with hypertension and hypercholesterolemia in stable CAD patients. In patients with AMI platelet-bound CyPA is significantly decreased.
    Platelets 06/2015; DOI:10.3109/09537104.2015.1051466 · 2.63 Impact Factor
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    M Mezger · K Göbel · P Kraft · S G Meuth · C Kleinschnitz · H F Langer
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    ABSTRACT: There is emerging evidence that platelets have an important role in inflammation beyond their involvement in hemostasis. Platelets can contribute to inflammatory reactions via crosstalk both with immune cells and endothelial cells. Inflamed vessels are characterized by the presence of activated endothelial cells. These activated endothelial cells upregulate receptors necessary for leukocyte recruitment, but also for the adhesion of platelets. Subsequently, immune cells can bind to platelets through adhesion receptors presented on the platelet surface, thus supporting leukocyte recruitment to the vessel wall. There are several neurological diseases associated with vascular inflammation including multiple sclerosis (MS) and stroke. Increased markers of platelet activation could be demonstrated in patients suffering from MS compared to healthy individuals. Reports from murine models indicate that platelets may be of importance for disease progression and severity by mediating leukocyte recruitment as one potential underlying mechanism. Blocking platelet function disease severity was considerably ameliorated. Moreover, processes of tissue remodelling may be influenced by platelet derived mediators. Whether a role of platelets for vascular inflammation can be extrapolated to further neurological diseases will have to be investigated in further in depth experimental and clinical trials. Platelets and platelet associated mechanisms may offer novel starting points to understand neurovascular diseases from a different point of view and to develop novel approaches to access the disease.
    Hamostaseologie 05/2015; 35(3). DOI:10.5482/HAMO-14-11-0071 · 1.59 Impact Factor
  • PLoS ONE 04/2015; 10(4):e0124606. DOI:10.1371/journal.pone.0124606 · 3.23 Impact Factor
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    ABSTRACT: The role of individual monocyte subsets in inflammatory cardiovascular diseases is insufficiently understood. Although the Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) regulates important processes for inflammation such as MMP-release, its expression and regulation on monocyte subsets has not been characterized. In this clinical study, blood was obtained from 80 patients with stable coronary artery disease (CAD), 49 with acute myocardial infarction (AMI) and 34 healthy controls. Monocytes were divided into 3 subsets: CD14(++)CD16(-) (low), CD14(++)CD16(+) (intermediate), CD14(+)CD16(++) (high) according to phenotypic markers analyzed by flow cytometry. Surface expression of EMMPRIN was evaluated and compared with CD36 and CD47 expression. In all patients, EMMPRIN expression was significantly different among monocyte subsets with the highest expression on "classical" CD14(++)CD16(-) monocytes. EMMPRIN was upregulated on all monocyte subsets in patients with AMI as compared to patients with stable CAD. Notably, neither CD47 nor CD36 revealed a significant difference in patients with AMI compared to patients with stable CAD. EMMPRIN could serve as a marker for classical monocytes, which is upregulated in patients with acute myocardial infarction. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Thrombosis Research 03/2015; 135(6). DOI:10.1016/j.thromres.2015.03.022 · 2.43 Impact Factor
  • International journal of cardiology 03/2015; 185:165-166. DOI:10.1016/j.ijcard.2015.03.128 · 6.18 Impact Factor
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    Henry M Nording · Peter Seizer · Harald F Langer
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    ABSTRACT: Platelets contribute to processes beyond thrombus formation and may play a so far underestimated role as an immune cell in various circumstances. This review outlines immune functions of platelets in host defense, but also how they may contribute to mechanisms of infectious diseases. A particular emphasis is placed on the interaction of platelets with other immune cells. Furthermore, this article outlines the features of atherosclerosis as an inflammatory vascular disease highlighting the role of platelet crosstalk with cellular and soluble factors involved in atheroprogression. Understanding, how platelets influence these processes of vascular remodeling will shed light on their role for tissue homeostasis beyond intravascular thrombosis. Finally, translational implications of platelet-mediated inflammation in atherosclerosis are discussed.
    Frontiers in Immunology 03/2015; 6:98. DOI:10.3389/fimmu.2015.00098
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    Johannes Patzelt · Admar Verschoor · Harald F Langer
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    ABSTRACT: Atherosclerosis and its late sequels are still the number one cause of death in western societies. Platelets are a driving force not only during the genesis of atherosclerosis, but especially in its late stages, as evidenced by complications such as arterial thrombosis, myocardial infarction, and ischemic stroke. Atherosclerosis is increasingly recognized as an inflammatory disease, influenced by various immune mechanisms. The complement system is part of our innate immune system, and its diverse roles in atherosclerosis have become evident over the past years. In this review we identify points of intersection between platelets and the complement system and discuss their relevance for atherosclerosis. Specifically, we will focus on roles for platelets in the onset as well as progression of the disease, a possible dual role for complement in the genesis and development of atherosclerosis, and review emerging literature revealing previously unrecognized cross-talk between platelets and the complement system and discuss its possible impact for atherosclerosis. Finally, we identify limitations of current research approaches and discuss perspectives of complement modulation in the control of the disease.
    Frontiers in Physiology 03/2015; 6:49. DOI:10.3389/fphys.2015.00049 · 3.50 Impact Factor
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    ABSTRACT: Surface expression of stromal cell-derived factor-1 (SDF-1, CXCL12) on platelets is enhanced during ischaemic events and plays an important role in peripheral homing of stem cells and myocardial repair mechanisms. SDF-1 effects are mediated through CXCR4 and CXCR7. Both CXCR4 and CXCR7 are surface expressed on human platelets and to a higher degree in patients with coronary artery disease (CAD) when compared with healthy controls. In this study, we investigated the prognostic role of platelet CXCR4- and CXCR7 surface expression in patients with symptomatic CAD. In a cohort study, platelet surface expression of CXCR4 and CXCR7 was measured by flow cytometry in 284 patients with symptomatic CAD at the time of percutaneous coronary intervention (PCI). The primary combined endpoint was defined as all-cause death and/or MI during 12 month follow-up. Secondary endpoints were defined as the single events of all-cause death and myocardial infarction (MI). We found significant differences of CXCR4 values in patients who developed a combined endpoint compared to event-free patients (mean MFI 3.17 vs. 3.44, 95% CI 0.09 - 0.45) and in patients who subsequently died (mean MFI 3.10 vs. 3.42, 95% CI 0.09 - 0.56). In multivariate Cox regression analysis lower platelet CXCR4 levels were independently and significantly associated with all cause mortality (HR 0.24, 95% CI 0.07 - 0.87) and the primary combined endpoint of all-cause death and/or MI (HR 0.30, 95% CI 0.13 - 0.72). These findings highlight a potential prognostic value of platelet expression CXCR4 on clinical outcomes in patients with CAD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 02/2015; 13(5). DOI:10.1111/jth.12870 · 5.55 Impact Factor
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    ABSTRACT: Cyclophilin A (CyPA) is secreted under inflammatory conditions by various cell types. Whereas the important role of intracellular CyPA for platelet function has been reported, the effect of extracellular CyPA on platelet function has not been investigated yet. Inhibition of extracellular CyPA through a novel specific inhibitor MM284 reduced thrombus after ferric chloride-induced injury in vivo. In vitro extracellular CyPA enhanced thrombus formation even in CyPA(-/-) platelets. Treatment of isolated platelets with recombinant CyPA resulted in platelet degranulation in a time- and dose-dependent manner. Inhibition of the platelet surface receptor extracellular matrix metalloproteinase inducer (cluster of differentiation 147) by an anticluster of differentiation 147 monoclonal antibody significantly reduced CyPA-dependent platelet degranulation. Pretreatment of platelets with CyPA enhanced their recruitment to mouse carotid arteries after arterial injury, which could be inhibited by an anticluster of differentiation 147 monoclonal antibody (intravital microscopy). The role of extracellular CyPA in adhesion could be confirmed by infusing CyPA(-/-) platelets in CyPA(+/+) mice and by infusing CyPA(+/+) platelets in CyPA(-/-) mice. Stimulation of platelets with CyPA induced phosphorylation of Akt, which could in turn be inhibited in the presence of phosphoinositid-3-kinase inhibitors. Akt-1(-/-) platelets revealed a markedly decreased degranulation on CyPA stimulation. Finally, ADP-induced platelet aggregation was attenuated by MM284, as well as by inhibiting paracrine-secreted CyPA without directly affecting Ca(2+)-signaling. Extracellular CyPA activates platelets via cluster of differentiation 147-mediated phosphoinositid-3-kinase/Akt-signaling, leading to enhanced adhesion and thrombus formation independently of intracellular CyPA. Targeting extracellular CyPA via a specific inhibitor may be a promising strategy for platelet inhibition without affecting critical functions of intracellular CyPA. © 2014 American Heart Association, Inc.
    Arteriosclerosis Thrombosis and Vascular Biology 12/2014; 35(3). DOI:10.1161/ATVBAHA.114.305112 · 5.53 Impact Factor
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    ABSTRACT: Inhibition of components of the complement system or of its receptorshas been postulated as a concept for primary andsecondary prevention in atherosclerosis and was applied in clinical trials. Although the anaphylatoxin-receptors C3aR and C5aR are commonly associated with inflammatory cells, in vitro studies suggested their expression also on platelets.
    Atherosclerosis 12/2014; 238(2). DOI:10.1016/j.atherosclerosis.2014.12.002 · 3.97 Impact Factor
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    ABSTRACT: Inflammation in the central nervous system (CNS) and disruption of its immune privilege are major contributors to the pathogenesis of multiple sclerosis (MS) and of its rodent counterpart, experimental autoimmune encephalomyelitis (EAE). We have previously identified developmental endothelial locus-1 (Del-1) as an endogenous anti-inflammatory factor, which inhibits integrin-dependent leukocyte adhesion. Here we show that Del-1 contributes to the immune privilege status of the CNS. Intriguingly, Del-1 expression decreased in chronic-active MS lesions and in the inflamed CNS in the course of EAE. Del-1-deficiency was associated with increased EAE severity, accompanied by increased demyelination and axonal loss. As compared with control mice, Del-1(-/-) mice displayed enhanced disruption of the blood-brain barrier and increased infiltration of neutrophil granulocytes in the spinal cord in the course of EAE, accompanied by elevated levels of inflammatory cytokines, including interleukin-17 (IL-17). The augmented levels of IL-17 in Del-1-deficiency derived predominantly from infiltrated CD8(+) T cells. Increased EAE severity and neutrophil infiltration because of Del-1-deficiency was reversed in mice lacking both Del-1 and IL-17 receptor, indicating a crucial role for the IL-17/neutrophil inflammatory axis in EAE pathogenesis in Del-1(-/-) mice. Strikingly, systemic administration of Del-1-Fc ameliorated clinical relapse in relapsing-remitting EAE. Therefore, Del-1 is an endogenous homeostatic factor in the CNS protecting from neuroinflammation and demyelination. Our findings provide mechanistic underpinnings for the previous implication of Del-1 as a candidate MS susceptibility gene and suggest that Del-1-centered therapeutic approaches may be beneficial in neuroinflammatory and demyelinating disorders.Molecular Psychiatry advance online publication, 11 November 2014; doi:10.1038/mp.2014.146.
    Molecular Psychiatry 11/2014; 20(7). DOI:10.1038/mp.2014.146 · 15.15 Impact Factor
  • Circulation 11/2014; 130(20):e173-4. DOI:10.1161/CIRCULATIONAHA.114.012504 · 14.95 Impact Factor
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    ABSTRACT: The Bcl-2 proteins Bax and Bak can permeabilize the outer mitochondrial membrane and commit cells to apoptosis. Pro-survival Bcl-2 proteins control Bax by constant retrotranslocation into the cytosol of healthy cells. The stabilization of cytosolic Bax raises the question whether the functionally redundant but largely mitochondrial Bak shares this level of regulation. Here we report that Bak is retrotranslocated from the mitochondria by pro-survival Bcl-2 proteins. Bak is present in the cytosol of human cells and tissues, but low shuttling rates cause predominant mitochondrial Bak localization. Interchanging the membrane anchors of Bax and Bak reverses their subcellular localization compared to the wild-type proteins. Strikingly, the reduction of Bax shuttling to the level of Bak retrotranslocation results in full Bax toxicity even in absence of apoptosis induction. Thus, fast Bax retrotranslocation is required to protect cells from commitment to programmed death.
    The EMBO Journal 11/2014; 34(1). DOI:10.15252/embj.201488806 · 10.75 Impact Factor
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    ABSTRACT: Background. Functional recovery and prognosis after acute coronary syndromes (ACS) are mainly driven by the extent of reperfusion injury and myocardial repair mechanisms. Transforming growth factor-beta 1 (TGF-β1) is critically involved in cardiac injury, repair and remodeling. In this study, we investigated the prognostic role of platelet TGF-β1 surface expression and circulating TGF-β1 levels in patients with coronary artery disease (CAD). Methods and results. Expression of TGF-β1 in platelets and circulating TGF-β1 levels were investigated by flow cytometry and ELISA, respectively, among patients with ACS and stable CAD undergoing percutaneous coronary intervention (PCI). In a cohort study, platelet and circulating TGF-β1 was measured in 299 patients with symptomatic CAD (stable CAD = 145, ACS = 154) at the time of PCI. The primary combined endpoint was defined as death and/or STEMI during 12-month follow-up. Platelets expressed TGF-β1 and circulating TGF-β1 showed a weak, but significant negative correlation. TGF-β1 surface expression was significantly elevated on platelets in ACS patients compared to patients with stable CAD (median MFI 13.4 vs. median MFI 11.7, p = 0.003). During follow-up, lower platelet expression of TGF-β1 was associated with all-cause mortality (median MFI 11.0 vs. median MFI 13.9, p = 0.011) as well as for the combined endpoint of death and/or STEMI, (median MFI 10.8 vs. median MFI 13.9, p = 0.006). In multivariate analysis platelet TGF-β1 expression was independently associated with the combined primary endpoint in the overall cohort (Hazard Ratio 0.31, 95% Confidence Interval 0.11-0.89, p = 0.029) and was strongly associated with prognosis in ACS patients. There was no significant association of circulating TGF-β1 levels neither with the presence of ACS nor the occurrence of the primary endpoint. Conclusion. These findings highlight a potential role of platelet expressed TGF-β1 in ACS and indicate a prognostic value of TGF-β1 on clinical outcomes in patients with acute coronary syndromes. Large scale studies are warranted to further evaluate the regulatory mechanisms of platelet TGF-β1 expression- and its prognostic impact in CAD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 10/2014; 237(2):754-759. DOI:10.1016/j.atherosclerosis.2014.10.021 · 3.97 Impact Factor
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    ABSTRACT: Targeted contrast-enhanced ultrasound (CEU) using microbubble agents is a promising non-invasive imaging technique to evaluate atherosclerotic lesions. In this study, we decipher the diagnostic and therapeutic potential of targeted-CEU with soluble glycoprotein (GP)-VI in vivo. Microbubbles were conjugated with the recombinant fusion protein GPVI-Fc (MBGPVI) that binds with high affinity to atherosclerotic lesions. MBGPVI or control microbubbles (MBC) were intravenously administered into ApoE(-/-) or wild type mice and binding of the microbubbles to the vessel wall was visualized by high-resolution CEU. CEU molecular imaging signals of MBGPVI were substantially enhanced in the aortic arch and in the truncus brachiocephalicus in ApoE(-/-) as compared to wild type mice. High-frequency ultrasound (HFU)-guided disruption of MBGPVI enhanced accumulation of GPVI in the atherosclerotic lesions, which may interfere with atheroprogression. Thus, we establish targeted-CEU with soluble GPVI as a novel non-invasive molecular imaging method for atherosclerosis. Further, HFU-guided disruption of GPVI-targeted microbubbles is an innovate therapeutic approach that potentially prevents progression of atherosclerotic disease.
    Biomaterials 10/2014; 36. DOI:10.1016/j.biomaterials.2014.09.016 · 8.31 Impact Factor
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    ABSTRACT: Objective: Monocyte infiltration is a critical step in the pathophysiology of plaque instability in coronary artery disease (CAD). Macrophage migration inhibitory factor (MIF) is involved in atherosclerotic plaque progression and instability leading to intracoronary thrombosis. Gremlin-1 (Grem1) has been recently identified as endogenous inhibitor of MIF. To date there are no data on the clinical impact of this interaction in cardiovascular patients. Methods and results: Plasma levels of MIF and Grem1 were determined by enzyme-linked immunoassay in patients with acute coronary syndromes (ACS, n = 120; stable CAD, n = 166 and healthy control subjects, n = 25). MIF levels were significantly increased in ACS compared to stable CAD and healthy control (ACS: median 2.85; IQR 3.52 ng/ml; versus SAP: median 1.22; IQR 2.99 ng/ml; versus healthy control: median 0.10; IQR 0.09 ng/ml, p < 0.001). Grem1 levels were significantly higher in ACS and stable CAD patients compared to healthy control (ACS: median 211.00; IQR 130.47 ng/ml; SAP: median 220.20; IQR 120.93 ng/ml, versus healthy control: median 90.57; IQR 97.68 ng/ml, p < 0.001). Grem1/MIF ratio was independently associated with ACS, whereas the single parameters were not associated with the presence of ACS. Furthermore, Grem1/MIF ratio was associated with angiographic signs of intracoronary thrombi and severity of thrombus burden. Conclusion: These novel findings suggest a potential role of Grem1/MIF ratio to indicate acuity of CAD and the grade of plaque stability. Prospective angiographic cohort studies involving plaque imaging techniques are warranted to further characterize the prognostic role of this novel risk marker in CAD patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 09/2014; 237(2):426-432. DOI:10.1016/j.atherosclerosis.2014.09.010 · 3.97 Impact Factor
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    ABSTRACT: Rationale: Macrophage migration inhibitory factor (MIF) is released upon platelet activation. Circulating MIF could potentially regulate platelets and thereby platelet-mediated inflammatory and regenerative mechanisms. However the effect of MIF on platelets is unknown. Objective: The current study evaluated MIF in regulating platelet survival and thrombotic potential. Methods and Results: MIF interacted with CXCR4-CXCR7 on platelets, defining CXCR7 as a hitherto unrecognized receptor for MIF on platelets. MIF internalized CXCR4, but unlike CXCL12 (SDF-1α), it did not phosphorylate Erk1/2 following CXCR4 ligation due to the lack of CD74 and failed in subsequent CXCR7 externalization. MIF did not alter the activation status of platelets. However, MIF rescued platelets from activation and BH3 mimetic-ABT-737-induced apoptosis in vitro via CXCR7 and enhanced circulating platelet survival when administered in vivo. The anti-apoptotic effect of MIF was absent in Cxcr7(-/-) murine embryonic cells but pronounced in CXCR7 transfected MDCK cells. This pro-survival effect was attributed to the MIF-CXCR7-initiated PI3K-Akt pathway. MIF induced CXCR7-Akt-dependent phosphorylation of BCL-2 antagonist of cell death (BAD) both in vitro and in vivo. Consequentially, MIF failed to rescue Akt(-/-) platelets from thrombin induced apoptosis when challenged ex vivo, also in prolonging platelet survival and in inducing BAD phosphorylation among Akt(-/-) mice in vivo. MIF reduced thrombus formation under arterial flow conditions in vitro and retarded thrombotic occlusion following FeCl3-induced arterial injury in vivo, an effect mediated through CXCR7. Conclusions: MIF interaction with CXCR7 modulates platelet survival and thrombotic potential both in vitro and in vivo, and thus could regulate thrombosis and inflammation.
    Circulation Research 09/2014; 115(11). DOI:10.1161/CIRCRESAHA.115.305171 · 11.09 Impact Factor
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    ABSTRACT: Background: Monocyte migration and their differentiation into macrophages critically regulate vascular inflammation and atherogenesis and are governed by macrophage migration inhibitory factor (MIF). Gremlin-1 binds to MIF. Current experimental evidences present Gremlin-1 as a potential physiological agent that might counter-regulate the inflammatory attributes of MIF. Methods and results: We found that Gremlin-1 inhibited MIF-dependent monocyte migration and adhesion to activated endothelial cells in flow chamber perfusion assay in vitro and to the injured carotid artery of WT and ApoE(-/-) mice in vivo as deciphered by intravital microscopy. Intravenous administration of Gremlin-1, but not of control protein, significantly reduced leukocyte recruitment towards the inflamed carotid artery of ApoE(-/-) mice. Besides, leukocytes from MIF-/- when administered into ApoE(-/-) mice showed lesser adhesion as compared to wild type. In the presence of Gremlin-1 however, adhesion of wild type, but not of MIF-/- leukocytes, to the carotid artery was significantly inhibited as compared to control. Gremlin-1 also inhibited the MIF-induced differentiation of monocytes into macrophages. Gremlin-1 substantially inhibited the antiapoptotic impact of MIF on monocytes against BH3 mimetic ABT-737-induced apoptosis as verified by Annexin V-binding, caspase 3 activity, and mitochondrial depolarization. Conclusions: Therefore Gremlin-1 can modulate MIF dependent monocyte adhesion, migration, differentiation and survival.
    International Journal of Cardiology 08/2014; 176(3). DOI:10.1016/j.ijcard.2014.08.051 · 6.18 Impact Factor
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    ABSTRACT: Platelet-derived SDF-1α (CXCL12) mediates inflammatory and regenerative mechanisms. The present study characterizes the effect of SDF-1α ligation in platelets. SDF-1α (0-100 μM) dose and time dependently caused internalization of its receptor CXCR4 (28.9±1.6 vs. 16.1±1.9 in SDF-1α-treated platelets), coupled to the surface externalization of CXCR7 (65.5±8 vs. 162.8±27.6 following SDF-1α treatment), both in vitro and in vivo. This was inhibited in the presence of AMD3100 (100 μM), CXCR4 blocking and vesicular transport inhibitors (brefeldin A, 10 μM; rapamycin, 100 nM). SDF-1α/CXCR-4-mediated CXCR7 translocation was significantly reduced by inhibitors of ERK1/2-(U0126-10 μM) and cyclophilinA (CyPA)-(NIM811-10 μM) by 28 and 46%, respectively. Further, SDF-1α-induced downstream phosphorylation of Erk1/2 led to CyPA-dependent ubiquitination of CXCR7, which is essential for its surface translocation. CyPA-PPIase-activity inhibitor NIM-811, Erk1/2, and E1-ligase inhibitor-(PYR-41-25 μM) significantly abolished SDF-1α-driven CXCR7 ubiquitination and subsequent surface translocation. SDF-1α induced CXCR7 ubiquitination, and its surface exposure was observed in wild-type murine platelets, but not in CyPA-deficient platelets. SDF-1α/CXCR4-CyPA-dependent CXCR7 translocation and its subsequent ligation attenuated activation-induced apoptosis both in vitro and when administered in vivo. This antiapoptotic effect of SDF-1α was abrogated by blocking CXCR7, also significantly affected in Cypa(-/-) platelets. Thus, we decipher a novel mechanism, whereby SDF-1α regulates relative receptor availability in circulating platelets and exerts its prosurvival benefits.-Chatterjee, M., Seizer, P., Borst, O., Schönberger, T., Mack, A., Geisler, T., Langer, H. F., May, A. E., Vogel, S., Lang, F., Gawaz, M. SDF-1α induces differential trafficking of CXCR4-CXCR7 involving cyclophilin A, CXCR7 ubiquitination and promotes platelet survival.
    The FASEB Journal 03/2014; 28(7). DOI:10.1096/fj.14-249730 · 5.48 Impact Factor
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    ABSTRACT: The co-stimulatory immune molecule CD40L figures prominently in a variety of inflammatory conditions including arterial disease. Recently, we made the surprising finding that CD40L mediates atherogenesis independently of its classic receptor CD40 via a novel interaction with the leukocyte integrin Mac-1. Here, we hypothesised that selective blockade of the CD40L-Mac-1 interaction may also retard restenosis. We induced neointima formation in C57/BL6 mice by ligation of the left carotid artery. Mice were randomised to daily intraperitoneal injections of either cM7, a small peptide selectively inhibiting the CD40L-Mac-1 interaction, scM7, a scrambled control peptide, or saline for 28 days. Interestingly, cM7-treated mice developed neointima of similar size compared with mice receiving the control peptide or saline as assessed by computer-assisted analysis of histological cross sections. These data demonstrate that the CD40L-Mac-1 interaction is not required for the development of restenosis. In contrast, CD40-deficient mice subjected to carotid ligation in parallel, developed significantly reduced neointimal lesions compared with respective wild-type controls (2872 ± 843 µm² vs 35469 ± 11870 µm²). Flow cytometry in CD40-deficient mice revealed reduced formation of platelet-granulocyte and platelet-inflammatory monocyte- aggregates. In vitro, supernatants of CD40-deficient platelet-leukocyte aggregates attenuated proliferation and increased apoptosis of smooth muscle cells. Unlike in the setting of atherosclerosis, CD40L mediates neointima formation via its classic receptor CD40 rather than via its recently described novel interaction with Mac-1. Therefore, selective targeting of CD40L-Mac-1 binding does not appear to be a favorable strategy to fight restenosis.
    Thrombosis and Haemostasis 03/2014; 112(2). DOI:10.1160/TH13-08-0653 · 5.76 Impact Factor

Publication Stats

4k Citations
679.28 Total Impact Points


  • 2005–2015
    • University of Tuebingen
      • Institute for Physiology
      Tübingen, Baden-Württemberg, Germany
  • 2006–2014
    • Universitätsklinikum Tübingen
      • • Internal Medicine III - Cardiology and circulatory disorders
      • • Department of Medicine
      Tübingen, Baden-Württemberg, Germany
  • 2008–2010
    • National Cancer Institute (USA)
      • Experimental Immunology Branch
      Maryland, United States
  • 2009
    • Otto-von-Guericke-Universität Magdeburg
      • Clinic for Cardiology, Angiology and Pneumology
      Magdeburg, Saxony-Anhalt, Germany
    • National Institutes of Health
      • Branch of Experimental Immunology
      Maryland, United States
    • NCI-Frederick
      Maryland, United States
  • 2007
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2004
    • Technische Universität München
      München, Bavaria, Germany