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Andreas Schober

Publications and source records attributed to Andreas Schober.

30 records · Page 2Linked to original sources
PubMed2004

Chemokines: key regulators of mononuclear cell recruitment in atherosclerotic vascular disease.

Understanding the increasingly complex role of chemokines in various manifestations of atherosclerotic vascular disease and the apparent redundancy in their expression requires improved concepts defining the specialization and cooperation of chemokines in regulating the recruitment of mononuclear cells to vascular lesions. In an attempt to elaborate such models, this review highlights recent insights into the functional role of chemokines in mediating distinct steps during the atherogenic recruitment of monocytes and T cells obtained in genetically deficient mice and in suitable models. A particular focus is placed on the contribution of platelet chemokines deposited on endothelium for monocyte arrest, on differences in the involvement of chemokines between recruitment to native lesions and to neointimal lesions after arterial injury, and on closely related functions of macrophage migration inhibitory factor, a cytokine with considerable structural homology to chemokines. As an evolving aspect of atherosclerotic vascular disease, a role of chemokines, foremost stromal cell-derived factor-1alpha, in the recruitment of mononuclear progenitors of vascular cells during neointimal hyperplasia, endothelial recovery, and angiogenesis is discussed. The functional diversity and pleiotropy of chemokines in and beyond mononuclear cell recruitment awaits further elucidation to enable therapeutic targeting of atherogenesis by context-specific blockade of nonoverlapping chemokine receptor pairs.

Animals↗
PubMed2004

Classic toxin-induced animal models of Parkinson's disease: 6-OHDA and MPTP.

Neurological disorders in humans can be modeled in animals using standardized procedures that recreate specific pathogenic events and their behavioral outcomes. The development of animal models of Parkinson's disease (PD) is important to test new neuroprotective agents and strategies. Such animal models of PD have to mimic, at least partially, a Parkinson-like pathology and should reproduce specific features of the human disease. PD is characterized by massive degeneration of dopaminergic neurons in the substantia nigra, the loss of striatal dopaminergic fibers and a dramatic reduction of the striatal dopamine levels. The formation of cytoplasmic inclusion bodies (Lewy bodies) in surviving dopaminergic neurons represents the most important neuropathological feature of PD. Furthermore, the massive striatal dopamine deficiency causes easily detectable motor deficits in PD patients, including bradykinesia, rigidity, and resting tremor, which are the cardinal symptoms of PD. Over the years, a broad variety of experimental models of PD were developed and applied in diverse species. This review focuses on the two most common "classical" toxin-induced PD models, the 6-hydroxy-dopamine (6-OHDA model) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, whereas in humans the PD pathogenesis follows a progressive course over decades. This discrepancy reflects one important and principal point of weakness related to most animal models. This review discusses the most important properties of 6-OHDA and MPTP, their modes of administration, and critically examines advantages and limitations of selected animal models. The new genetic and environmental toxin models of PD (e.show $132#g. rotenone, paraquat, maneb) are discussed elsewhere in this "special issue."

Animals↗
PubMed2004

Neointimal smooth muscle cells display a proinflammatory phenotype resulting in increased leukocyte recruitment mediated by P-selectin and chemokines.

Leukocyte recruitment is crucial for the response to vascular injury in spontaneous and accelerated atherosclerosis. Whereas the mechanisms of leukocyte adhesion to endothelium or matrix-bound platelets have been characterized, less is known about the proadhesive role of smooth muscle cells (SMCs) exposed after endothelial denudation. In laminar flow assays, neointimal rat SMCs (niSMCs) supported a 2.5-fold higher arrest of monocytes and "memory" T lymphocytes than medial SMCs, which was dependent on both P-selectin and VLA-4, as demonstrated by blocking antibodies. The increase in monocyte arrest on niSMCs was triggered by the CXC chemokine GRO-alpha and fractalkine, whereas "memory" T cell arrest was mediated by stromal cell-derived factor (SDF)-1alpha. This functional phenotype was paralleled by a constitutively increased mRNA and surface expression of P-selectin and of relevant chemokines in niSMCs, as assessed by real-time PCR and flow cytometry. The increased expression of P-selectin in niSMCs versus medial SMCs was associated with enhanced NF-kappaB activity, as revealed by immunofluorescence staining for nuclear p65 in vitro. Inhibition of NF-kappaB by adenoviral IkappaBalpha in niSMCs resulted in a marked reduction of increased leukocyte arrest in flow. Furthermore, P-selectin expression by niSMCs in vivo was confirmed in a hypercholesterolemic mouse model of vascular injury by double immunofluorescence and by RT-PCR after laser microdissection. In conclusion, we have identified a NF-kappaB-mediated proinflammatory phenotype of niSMCs that is characterized by increased P-selectin and chemokine expression and thereby effectively supports leukocyte recruitment.

Animals↗
PubMed2004

Dexamethasone and restenosis after coronary stent implantation: new indication for an old drug?

Restenosis after stent implantation is mainly characterized by an inflammatory response to the procedural injury and an intense fibrocellular response including smooth muscle cell (SMC) proliferation. After angioplasty alone, the restenosis process also involves thrombus formation and negative remodeling. Due to the pleiotropic mode of action exerted by glucocorticoids which include profound anti-inflammatory and immunosuppressive effects, direct inhibition on SMC proliferation and apoptosis, their potential in the prevention of restenosis has gained widespread interest. Over the last decade, preclinical and clinical data have not been able to conclusively document a robust therapeutic effect on restenosis after angioplasty or stent implantation. Only recently, preclinical data and limited observations in humans using drug eluting stents for local drug delivery have suggested beneficial effects of dexamethasone on neointimal proliferation. Randomized clinical trials using local drug delivery are expected to start in the near future. In the light of these ongoing developments, this review summarizes the pathophysiological basis of glucocorticoid action in the context of restenosis, provides an overview of the animal data available and discusses the clinical results that have been gathered over the last decade with particular emphasis on dexamethasone.

Angioplasty, Balloon, Coronary↗
PubMed2003

Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein E-deficient mice.

BACKGROUND: Macrophage migration inhibitory factor (MIF), a cytokine that controls cell-mediated inflammatory responses, is upregulated in atherogenesis; however, its functional contribution to lesion development has not been evaluated. METHODS AND RESULTS: We studied the role of MIF on neointima lesion formation after wire-induced injury of carotid arteries in apolipoprotein E-deficient (apoE(-/-)) mice. Immunohistochemistry revealed that MIF expression was detectable in endothelial cells before injury and upregulated in smooth muscle cells (SMCs) 24 hours after endothelial denudation. Three weeks after injury, MIF was predominantly found in endothelial cells and macrophage-derived foam cells. Neutralizing MIF with a monoclonal antibody resulted in a marked reduction of neointimal macrophages and inhibited transformation of macrophages into foam cells. Conversely, the content of SMCs and of collagen in the neointima were increased, amounting to a slight but not significant reduction in neointima and media size after 3 weeks of MIF monoclonal antibody treatment. Notably, serum levels of the cytokines IL-2, IL-4, IL-6, IL-10, and tumor necrosis factor were increased in MIF monoclonal antibody-treated mice. In vitro flow assays revealed that MIF pretreatment of aortic endothelium enhanced monocyte recruitment and that the monocyte arrest induced by oxidized LDL is mediated by endothelial MIF, as shown by monoclonal antibody inhibition. CONCLUSIONS: Inhibition of MIF resulted in a shift in the cellular composition of neointimal plaques toward a stabilized phenotype with reduced macrophage/foam cell content and increased SMC content. This might be attributable to a reduction of monocyte recruitment mediated by endothelial MIF.

Animals↗
PubMed2003

Crucial role of stromal cell-derived factor-1alpha in neointima formation after vascular injury in apolipoprotein E-deficient mice.

BACKGROUND: Recent evidence indicates that stromal cell-derived factor-1alpha (SDF-1alpha) is expressed in human atherosclerotic plaques, whereas high plasma levels are clinically associated with stable coronary artery disease. Herein, we investigate the involvement of SDF-1alpha in neointimal formation after vascular injury. METHODS AND RESULTS: SDF-1alpha was detected by immunohistochemistry in carotid arteries of apolipoprotein E-deficient (apoE-/-) mice at various stages of neointima formation after wire-induced injury. Double immunofluorescence revealed that SDF-1alpha staining was mostly confined to smooth muscle cells (SMCs). Furthermore, SDF-1alpha plasma levels peaked 1 day after vascular injury. Treatment of apoE-/- mice after carotid injury with a neutralizing SDF-1alpha monoclonal antibody for 3 weeks reduced neointimal lesion area by 44% (n=5, P<0.05) compared with isotype control. In SDF-1alpha antibody-treated apoE-/- mice, neointimal SMC content was decreased (21.7+/-2% versus 39.4+/-4%, n=5, P=0.005), whereas the relative content of neointimal macrophages remained unchanged. As shown by flow cytometry, carotid injury resulted in a marked expansion of circulating Sca-1+lineage- progenitor cells (PBPCs) in the peripheral blood of apoE-/- mice after 1 day, which was mediated by SDF-1alpha. Systemic injection of isolated PBPCs after vascular injury demonstrated their recruitment to neointimal lesions, where they can adopt an SMC-like phenotype. CONCLUSIONS: SDF-1alpha plays an instrumental role in neointimal formation after vascular injury in apoE-/- mice by regulating neointimal SMC content. This contribution appears to be attributable to SDF-1alpha-dependent recruitment of circulating SMC progenitor cells.

Angioplasty↗
PubMed2002

Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E.

We studied whether circulating activated platelets and platelet-leukocyte aggregates cause the development of atherosclerotic lesions in apolipoprotein-E-deficient (Apoe(-/-)) mice. Circulating activated platelets bound to leukocytes, preferentially monocytes, to form platelet-monocyte/leukocyte aggregates. Activated platelets and platelet-leukocyte aggregates interacted with atherosclerotic lesions. The interactions of activated platelets with monocytes and atherosclerotic arteries led to delivery of the platelet-derived chemokines CCL5 (regulated on activation, normal T cell expressed and secreted, RANTES) and CXCL4 (platelet factor 4) to the monocyte surface and endothelium of atherosclerotic arteries. The presence of activated platelets promoted leukocyte binding of vascular cell adhesion molecule-1 (VCAM-1) and increased their adhesiveness to inflamed or atherosclerotic endothelium. Injection of activated wild-type, but not P-selectin-deficient, platelets increased monocyte arrest on the surface of atherosclerotic lesions and the size of atherosclerotic lesions in Apoe(-/-) mice. Our results indicate that circulating activated platelets and platelet-leukocyte/monocyte aggregates promote formation of atherosclerotic lesions. This role of activated platelets in atherosclerosis is attributed to platelet P-selectin-mediated delivery of platelet-derived proinflammatory factors to monocytes/leukocytes and the vessel wall.

Animals↗
PubMed2002

Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury.

BACKGROUND: Chemokines expressed on atherosclerotic endothelium or deposited by activated platelets have been implicated in monocyte recruitment during atherogenesis and restenosis. Although the involvement of P-selectin in these processes is evident from studies in knockout mice, it has not been elucidated whether delivery of platelet chemokines requires P-selectin, thus serving as a P-selectin-dependent effector function. METHODS AND RESULTS: Using immunofluorescence and laminar flow assays, we found that the deposition of the platelet-derived chemokine RANTES and monocyte arrest subsequently triggered by RANTES immobilized on inflamed endothelium are more efficient after preperfusion than after static preincubation of platelets and appear to depend on interactions of platelet but not endothelial P-selectin. This was revealed by the effects of P-selectin antibodies and comparison of P-selectin-deficient and wild-type platelets. Immunohistochemistry detected a substantial luminal expression of RANTES on neointimal lesions in wire-injured carotid arteries of apolipoprotein E (apoE)-deficient mice but not of mice with a combined deficiency in apoE and P-selectin (or platelet P-selectin). As assessed by histomorphometry, treatment of apoE-deficient mice with the RANTES receptor antagonist Met-RANTES markedly reduced neointimal plaque area and macrophage infiltration. CONCLUSIONS: Our data suggest that RANTES deposition and subsequent monocyte arrest are promoted by platelet P-selectin and involved in wire-induced intimal hyperplasia, and that blocking RANTES receptors attenuates neointima formation and macrophage infiltration. This mechanism represents an important component explaining the protection against neointimal growth in P-selectin-deficient mice and may represent a novel approach to the treatment of restenosis or atherosclerosis by the administration of chemokine receptor antagonists.

Animals↗
PubMed2002

Fibroblast growth factor-2 requires glial-cell-line-derived neurotrophic factor for exerting its neuroprotective actions on glutamate-lesioned hippocampal neurons.

FGF-2 is a potent neurotrophic factor for several populations of CNS neurons and has been shown to protect hippocampal neurons from glutamate-induced cell death in vitro and in vivo. Mechanisms underlying the neurotrophic and protective actions of FGF-2 have been resolved only in part. Using glutamate-treated cultured hippocampal neurons we show that FGF-2 shares its neuroprotective capacity with GDNF. Hippocampal neurons express glial-cell-line-derived neurotrophic factor (GDNF), its receptors c-Ret and the lipid-anchored GDNF family receptor-alpha1 (GFRalpha-1), and the FGF receptor 1 (FGFR I). Neutralizing antibodies to GDNF abolish the neuroprotective effect of FGF-2. In support of the notion that GDNF is required to permit the protective effects of FGF-2 we find that FGF-2 up-regulates GDNF and GFRalpha-1 in hippocampal neurons. Furthermore, FGF-2-induced GDNF causes enhanced phosphorylation of c-Ret and the signaling components Akt and Erk. A putative downstream target of FGF-2 and GDNF are bcl-2 gene family members, whose mRNAs are differentially up-regulated by the two factors. Together, these data suggest that GDNF is an important protective factor for glutamate-lesioned hippocampal neurons and an essential mediator of the neuroprotective actions of FGF-2.

Animals↗
PubMedDate not supplied

TGF-beta and the regulation of neuron survival and death.

Transforming growth factor-betas (TGF-betas) constitute a superfamily of multifunctional cytokines with important implications in morphogenesis, cell differentiation, and tissue remodeling. In the developing nervous system, TGF-beta2 and -beta3 occur in radial and astroglial cells as well as in many populations of postmitotic, differentiating neurons. TGF-beta1 is restricted to the choroid plexus and meninges. In addition to functions related to glial cell maturation and performances, TGF-beta2 and -beta3 are important regulators of neuron survival. In contrast to neurotrophic factors, as for example, neurotrophins, TGF-betas are most likely not neurotrophic by themselves. However, they can dramatically increase the potency of select neurotrophins, fibroblast growth factor-2, ciliary neurotrophic factor, and glial cell line-derived neurotrophic factor (GDNF). In the case of GDNF, we have shown that GDNF fails to promote the survival of highly purified neuron populations in vitro unless it is supplemented with TGF-beta. This also applies to the in vivo situation, where antibodies to all three TGF-beta isoforms fully prevent the trophic effect of GDNF on axotomized, target-deprived neurons. In addition to the TGF-beta isoforms -beta2 and -beta3, other members of the TGF-beta superfamily are expressed in the nervous system having important roles in embryonic patterning, cell migration, and neuronal transmitter determination. We have cloned and expressed a novel TGF-beta, named growth/differentiation factor-15 (GDF-15). GDF-15 is synthesized in the choroid plexus and released into the CSF, but also occurs in all regions investigated of the developing and adult brain. GDF-15 is a potent trophic factor for developing and 6-OHDA-lesioned midbrain dopaminergic neurons in vitro and in vivo, matching the potency of GDNF.

Animals↗
PubMedDate not supplied

Mechanisms of monocyte recruitment in vascular repair after injury.

The inflammatory response to acute vessel wall injury has been increasingly recognized to play a decisive role in neointima formation. In particular, the exuberant infiltration with monocytes aggravates neointimal growth and can thereby promote restenosis. The adhesion of circulating monocytes to the site of mechanical injury represents the key event in monocyte recruitment, and this review highlights recent insights into the molecular mechanisms of monocyte adhesion throughout the course of neointimal growth. An acute and a chronic phase of monocyte recruitment after vascular injury can be discerned. The adhesion of platelets to the denuded subendothelial matrix is the hallmark of the acute phase providing an adhesive substrate for monocytes, whereas chronic monocyte recruitment is regulated by the interaction with neointimal smooth muscle cells and recovering endothelial cells. Clearly, the mechanisms of monocyte rolling and adhesion differ considerably between these diverse substrates. This review is particularly focused on the contribution of chemokines and adhesion molecules to monocyte recruitment to injured vessels according to the different stages of neointimal growth, and on closely related functions of the chemokine-like molecule macrophage migration inhibitory factor. Understanding the complex molecular interactions of the injured vessel wall with circulating monocytes may enable therapeutic targeting to prevent the development of restenosis.

Animals↗