SDF-1 genotype influences insulin-dependent mobilization of adult progenitor cells in type 2 diabetes.
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Blood Glucose↗
Biomedical subjects
Angelika Bierhaus
Publications and source records attributed to Angelika Bierhaus.
Angiostatin is a novel anti-inflammatory factor by inhibiting leukocyte recruitment.
Angiogenesis and inflammation are closely related biologic processes in wound healing and the responses to vascular injury as well as in cardiovascular diseases; however, the molecular connections are poorly defined. In particular, it is yet unclear whether endogenous factors can regulate both angiogenesis and inflammation. Here, we show that the endogenous angiogenesis inhibitor, angiostatin (containing kringle domains 1-4 of plasminogen), serves an anti-inflammatory role, since the kringles 1-3 and its kringle 4 directly interact with leukocyte beta1- and beta2-integrins, respectively. In particular, a specific interaction between kringle 4 and alphaMbeta2-integrin (Mac-1) but not leukocyte function antigen 1 (LFA-1) was identified. Angiostatin thereby inhibited beta1- and beta2-integrin-mediated adhesion of leukocytes to extracellular matrix proteins and the endothelium as well as their transmigration through the endothelium in vitro. Moreover, angiostatin blocked the peritonitis-induced neutrophil emigration in vivo. In addition, through its interaction with Mac-1, angiostatin reduced activation of the proinflammatory transcription factor nuclear factor kappaB (NFkappaB), as well as the NFkappaB-related expression of tissue factor, a potent initiator of hemostasis following vascular injury. Finally, angiostatin forms were generated in vivo following skin injury/inflammation and were detectable during the following entire period of wound healing peaking at the terminal phase of the healing process. Taken together, over and above inhibition of neovascularization, angiostatin was identified as an antiadhesive/anti-inflammatory substance. These observations could provide the basis for new therapeutic applications of angiostatin to target chronic inflammatory processes in different pathologic situations.
Angiogenesis Inhibitors↗
Tuning the volume of the immune response: strength and persistence of stimulation determine migration and cytokine secretion of dendritic cells.
Migration to lymph nodes and secretion of cytokines are critical functions of mature dendritic cells (DCs); however, these 2 functions are not necessarily linked. This is the first report showing that quantitative differences in identical signaling pathways determine DC migration and cytokine secretion. Using different polymerized forms of CD40 ligand, we demonstrate that the strength and persistence of CD40 signaling can induce either function. Induction of monocyte-derived DC (MoDC) migration required a weak and transient CD40 signal, whereas strong and persistent CD40 signaling blocked migration and biased toward cytokine secretion. In contrast to MoDCs, CD40 activation of CD1c+ peripheral blood DCs (PBDCs) induced a nonpersistent, intracellular signaling profile resulting in migratory-type DCs unable to secrete interleukin-12p70 (IL-12p70). Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38K activation synergistically mediated cytokine secretion, whereas migration was enhanced by p38K activation but reduced by persistent ERK1/2 activity. This model of signal strength and persistence also applied when stimulating DCs with intact microbes. Thus, a novel concept emerges in which the type of immune response induced by DCs is tuned by the strength and persistence of DC activating signals.
CD40 Antigens↗
Receptor for advanced glycation endproduct (RAGE)-mediated nuclear factor-kappaB activation in vasculitic neuropathy.
Binding of ligands to the receptor for advanced glycation endproducts (RAGE) results in activation of the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) and subsequent expression of NF-kappaB-regulated cytokines. In order to determine whether engagement of RAGE contributes to the pathogenesis of vasculitic neuropathy, we studied the presence of the RAGE ligand N(epsilon)-(carboxymethyl)lysine (CML), the receptor itself, NF-kappaB, and interleukin-6 (IL-6) in sural nerve biopsies of 12 patients with vasculitic neuropathies and 12 controls. In the patients, CML, RAGE, NF-kappaB, and IL-6 were localized in mononuclear cells, epineurial and endoneurial vessels and the perineurium. CML, RAGE, NF-kappaB, and IL-6 were expressed by CD4(+), CD8(+), and CD68(+) cells invading the nerves. Controls showed only weak staining. These data suggest that the RAGE pathway plays a critical proinflammatory role in vasculitic neuropathy.
Adult↗
[AGE-RAGE: a hypothesis or a mechanism?].
Acausal relation between hyperglycemia and accelerated atherosclerosis has been recently suggested. The AGE-RAGE interaction is a potential mechanism underlying the accelerated atherosclerosis. Hyperglycemia causes via nonenzymatic glycation the formation of AGEs (advanced glycation endproducts). AGEs as well as other ligands like S100/Calgranulin and Amphoterin mediate receptor-independent and -dependent (via the interaction with RAGE) effects. The ligand-RAGE-interaction results in an activation of NF-kappaB, increased expression of cytokines, chemokines, and adhesion molecules and induces oxidative stress. A relevant role of the ligand-RAGE-interaction has been demonstrated in in vivo studies, both for the accelerated atherosclerosis and increased neointima formation in diabetes mellitus. Recent data analysing atherosclerotic lesions of diabetic patients provide further evidence for the pathogenetic role of the RAGE-ligand-interaction. In addition, new experimental data established that AGEs interact with other receptors than RAGE, while RAGE interacts with a diverse group of ligands. Thus, further studies are needed for the characterization of the ligand-RAGE-interaction. These studies will provide a rationale for the development of new therapeutic approaches for accelerated atherosclerosis in diabetes mellitus.
Animals↗
Lack of association between polymorphisms of the toll-like receptor 4 gene and cerebral ischemia.
Toll-like receptor-4 (TLR4), an important mediator of the innate immune response, is expressed in atherosclerotic lesions. The common single nucleotide exchange (Asp299Gly) of the TLR4 gene has been previously reported to impair TLR4 function and to be associated with a decreased risk of carotid atherosclerosis. Therefore, we aimed to detect the potential impact of TLR4 genotypes on the risk of cerebral ischemia. We studied the prevalence of two common polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) in 3 independent study populations: (1.) in a cross-sectional study including 769 patients either with type 1 or type 2 diabetes mellitus, of whom 56 (7.2%) had a history of cerebral ischemia (study 1), (2.) a case-control study (study 2) including 128 consecutive patients with cerebral ischemia, mean age 60 +/- 10.9 years and 139 control subjects, and (3.) a case-control study (study 3) including 171 young adults aged < 50 years with cerebral ischemia and 204 control individuals. In all subjects, Asp299Gly and Thr399Ile were detected by restriction length analysis. The prevalence of the TLR4 genotypes was essentially the same between patients with cerebral ischemia and control subjects in all 3 study populations. Furthermore, there was also no association with the subgroup of atherosclerotic stroke in both case-control studies populations. Although TLR4 polymorphisms are associated with a decreased risk of carotid atherosclerotic lesions, our findings indicate that they do not influence the prevalence of cerebral ischemia. This implies that the Asp299Gly TLR4-allele might have a protective role in carotid atherosclerosis, but not in cerebral ischemia.
Adult↗
RAGE (receptor for advanced glycation end products): a central player in the inflammatory response.
The present review focuses on the role of RAGE, the "receptor for advanced glycation end products", in the inflammatory response. RAGE is a multiligand receptor that propagates cellular dysfunction in several inflammatory disorders, in tumors and in diabetes. RAGE is expressed at low levels in normal tissues, but becomes upregulated at sites where its ligands accumulate. RAGE may play a dual role in the inflammatory response: (i) interaction of RAGE on leukocytes or endothelial cells (ECs) with its ligands results in cellular activation involving the transcription factor NF-kappaB; (ii) on the other hand, RAGE on ECs may function as an adhesive receptor that directly interacts with leukocyte ss2-integrins, thereby directly being involved in inflammatory cell recruitment. These different aspects are discussed in the present review.
Animals↗
Antiangiogenic properties of low molecular weight heparin - does tissue factor provide the answer?
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Angiogenesis Inhibitors↗
Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily.
Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-kappaB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-kappaBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-kappaB and NF-kappaB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-kappaB activation was blunted in RAGE-null (RAGE(-/-)) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE(-/-) mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-kappaB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches.
Animals↗
Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response.
While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation.
Animals↗
Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with a reduced prevalence of diabetic neuropathy in patients with type 2 diabetes.
OBJECTIVE: To establish whether single nucleotide polymorphisms (Asp299Gly and Thr399Ile) of the toll-like receptor 4 have an association with late diabetic complications. RESEARCH DESIGN AND METHODS: The study was conducted in 246 type 1 and 530 type 2 diabetic patients. The alleles of both polymorphisms were detected using PCR and subsequent cleavage by NcoI and HinfI restriction endonucleases. RESULTS: No difference was found between type 1 and type 2 diabetic patients in the prevalence of alleles of the Asp299Gly and Thr399Ile polymorphisms. In most cases, the alleles Gly299 and Ile399 occurred in a co-segregatory manner. The prevalence of the Gly299/Ile399 haplotype was 10.6 and 12.1% in type 1 and type 2 diabetic patients, respectively (P = 0.63). No association with diabetic nephropathy or diabetic neuropathy was found in type 1 diabetic patients. In type 2 diabetic patients, however, heterozygote carriers of the Asp299Gly and Thr399Ile genotypes had a significantly reduced prevalence of diabetic neuropathy (odds ratio 0.35 [95% CI 0.19-0.61]; P = 0.0002); no association with diabetic nephropathy was found. CONCLUSIONS: Our data indicate that Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with reduced prevalence of diabetic neuropathy in type 2, but not in type 1, diabetes. Thus different mechanisms may be involved in the pathophysiology of diabetic neuropathy in type 1 and type 2 diabetes.
Amino Acid Substitution↗
Decreased plasma lipoprotein lipase in hypoadiponectinemia: an association independent of systemic inflammation and insulin resistance.
OBJECTIVE: Adiponectin is a plasma protein expressed in adipose tissue. Hypoadiponectinemia is associated with low HDL cholesterol and high plasma triglycerides, which also characterize lipoprotein lipase (LPL) deficiency syndromes. Recently, dramatically increased LPL activity was reported in mice overexpressing adiponectin. We therefore speculated that adiponectin may directly affect LPL in humans. RESEARCH DESIGN AND METHODS: We measured plasma adiponectin and postheparin LPL in 206 nondiabetic men and in a second group of 110 patients with type 2 diabetes. Parameters were correlated with markers of systemic inflammation (C-reactive protein [CRP]) and insulin resistance (homeostatis model assessment of insulin resistance [HOMA-IR]). RESULTS: Nondiabetic subjects with decreased plasma adiponectin had lower LPL activity (r=0.42, P <0.0001). This association of plasma adiponectin with LPL activity was confirmed in the second group of patients with type 2 diabetes (r=0.37, P <0.0001). Multivariate analysis revealed that adiponectin was the strongest factor influencing LPL activity, accounting for 23% of the variation in LPL activity in nondiabetic subjects and for 26% of the variation in LPL activity in type 2 diabetic patients. These associations were independent of plasma CRP and HOMA-IR. CONCLUSIONS: These results demonstrate an association of decreased postheparin LPL activity with low plasma adiponectin that is independent of systemic inflammation and insulin resistance. Therefore, LPL may represent a link between low adiponectin levels and dyslipidemia in both nondiabetic individuals and patients with type 2 diabetes.
Adiponectin↗
The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment.
The pattern recognition receptor, RAGE (receptor for advanced glycation endproducts), propagates cellular dysfunction in several inflammatory disorders and diabetes. Here we show that RAGE functions as an endothelial adhesion receptor promoting leukocyte recruitment. In an animal model of thioglycollate-induced acute peritonitis, leukocyte recruitment was significantly impaired in RAGE-deficient mice as opposed to wild-type mice. In diabetic wild-type mice we observed enhanced leukocyte recruitment to the inflamed peritoneum as compared with nondiabetic wild-type mice; this phenomenon was attributed to RAGE as it was abrogated in the presence of soluble RAGE and was absent in diabetic RAGE-deficient mice. In vitro, RAGE-dependent leukocyte adhesion to endothelial cells was mediated by a direct interaction of RAGE with the beta2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with beta1-integrins. The RAGE-Mac-1 interaction was augmented by the proinflammatory RAGE-ligand, S100-protein. These results were corroborated by analysis of cells transfected with different heterodimeric beta2-integrins, by using RAGE-transfected cells, and by using purified proteins. The RAGE-Mac-1 interaction defines a novel pathway of leukocyte recruitment relevant in inflammatory disorders associated with increased RAGE expression, such as in diabetes, and could provide the basis for the development of novel therapeutic applications.
Animals↗
[Osteoporosis and cardiovascular disease--two sides of the same coin?].
BACKGROUND: Osteoporosis and cardiovascular disease have numerous epidemiologic changes, health economic consequences, and molecular mechanisms in common, which are highlighted in this short review. EPIDEMIOLOGY AND CLINICAL STUDIES: The incidence of osteoporosis and cardiovascular disease is increasing in western societies, and genetic background, nutrition and psychologic factors play important roles in the pathogenesis of both diseases. The presence of a decreased bone mass or osteoporotic vertebral fractures are associated with an increased cardiovascular mortality. Calcaneal bone loss of 1 SD (standard deviation) as measured by osteodensitometry is associated with a 1.31 times increased risk for the occurrence of stroke. MOLECULAR MECHANISMS: The observed increase in interleukin-6 and tumor necrosis factor serum concentrations during the menopause contributes to osteoporotic bone loss and is associated with arteriosclerosis. Furthermore, the presence of hydroxyapatite in arteriosclerotic plaques supports the notion of common pathogenetic mechanisms for both, osteoporosis and arteriosclerosis. Osteopontin, bone GLA protein and bone morphogenetic protein-2, which have first been isolated from the organic bone matrix, are also present in arteriosclerotic plaques. 1,25-dihydroxycholecalciferol potently stimulates bone matrix mineralization and is also a negative regulator of the renin-angiotensin system; therefore vitamin D(3) deficiency in addition to bone metabolism also affects blood pressure. Osteoporosis and arteriosclerosis develop in mice lacking the osteoprotegerin gene and also in klotho gene knockout mice. CONCLUSION: Diagnosis of osteopenia, osteoporosis and osteoporotic vertebral or hip fractures indicates the presence of an increased cardiovascular risk which needs to be addressed by the physician who cares for patients with osteoporosis. The experimental finding of an osteoanabolic effect of statins supports the possibility of common pathogenetic disturbances which may be responsible for the simultaneous and frequent manifestation of osteoporosis and arteriosclerosis in elderly patients.
Animals↗
c-Fos-driven transcriptional activation of transforming growth factor beta-1: inhibition of high glucose-induced promoter activity by thiazolidinediones.
The peroxisome proliferator-activated receptor gamma activating compounds thiazolidinedione (TZD) have been shown to inhibit diabetes-induced glomerular transforming growth factor-beta1 (TGF-beta1) expression, thereby ameliorating diabetic nephropathy. Here we examined the hypothesis that TZDs block high glucose-induced TGF-beta1 gene activation by interaction with the activated protein kinase C-c-Fos-TGF-beta1 promoter cascade in mesangial cells. The TZD compounds troglitazone and rosiglitazone completely prevented the high glucose induction of both TGF-beta1 promoter activity and elevation in nuclear c-Fos protein levels. The scavenging properties of troglitazone were shown not to be responsible for this inhibitory action, because hydrogen peroxide-mediated stimulation of TGF-beta1 promoter activity was not blocked. TZD-treatment did not interfere with the transcriptional activity of c-Fos responsible for stimulation of the TGF-beta1 promoter. The findings suggest a molecular mechanism by which TZD-treatment reduces specifically high glucose-induced, c-Fos-mediated gene activation, since phorbol ester-induced c-Fos mRNA and protein expression and subsequent elevation of TGF-beta1 mRNA expression were not prevented by TZDs.
Animals↗
Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.
Three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia induced vascular damage (the hexosamine pathway, the advanced glycation end product (AGE) formation pathway and the diacylglycerol (DAG)-protein kinase C (PKC) pathway) are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. We have discovered that the lipid-soluble thiamine derivative benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-kappaB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-kappaB activation by activating transketolase, and also prevented experimental diabetic retinopathy. The ability of benfotiamine to inhibit three major pathways simultaneously might be clinically useful in preventing the development and progression of diabetic complications.
Animals↗
A mechanism converting psychosocial stress into mononuclear cell activation.
Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor kappaB (NF-kappaB). Therefore, NF-kappaB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-kappaB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-kappaB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-kappaB-controlled beta-globin transgene were stressed by immobilization. Immobilization resulted in increased beta-globin expression, which could be reduced in the presence of the alpha1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-kappaB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-kappaB and NF-kappaB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by alpha(1)- and beta-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-kappaB in vitro and in vivo. Activation of NF-kappaB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.
Adrenocorticotropic Hormone↗
New treatments for diabetic neuropathy: pathogenetically oriented treatment.
Although there is clear evidence from experimental diabetic neuropathy (DN) models that the multiple pathways involved in neuronal degeneration cause overproduction of reactive oxygen species, oxidative stress, and cellular dysfunction, therapeutic approaches addressing these mechanisms have not yet provided a basis for a successful treatment of patients with DN. This review discusses the current knowledge on the pathomechanisms of unchecked reactive oxygen species accumulation, implications for specific treatment, and the need for carefully designed experimental studies and clinical trials closing the gap between promising results in experimental DN and its implementation into a pathogenetically oriented treatment.
Diabetic Neuropathies↗