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  • ENDOTHELIAL-CELLS  (5)
  • 1
    Keywords: ENDOTHELIAL-CELLS ; TRANSCRIPTION FACTORS ; OXIDATIVE-STRESS ; CARDIOVASCULAR-DISEASE ; C-REL ; DIABETIC-NEPHROPATHY ; CORONARY-ARTERY-DISEASE ; TISSUE FACTOR EXPRESSION ; DOUBLE-KNOCKOUT MICE ; PSYCHOLOGICAL STRESS
    Abstract: Psychosocial stress has been shown to be a contributing factor in the development of atherosclerosis. Although the underlying mechanisms have not been elucidated entirely, it has been shown previously that the transcription factor nuclear factor-kappaB (NF-kappaB) is an important component of stress-activated signaling pathway. In this study, we aimed to decipher the mechanisms of stress-induced NF-kappaB-mediated gene expression, using an in vitro and in vivo model of psychosocial stress. Induction of stress led to NF-kappaB-dependent expression of proinflammatory (tissue factor, intracellular adhesive molecule 1 [ICAM-1]) and protective genes (manganese superoxide dismutase [MnSOD]) via p50, p65 or cRel. Selective inhibition of the different subunits and the respective kinases showed that inhibition of cRel leads to the reduction of atherosclerotic lesions in apolipoprotein(-/-) (ApoE(-/-)) mice via suppression of proinflammatory gene expression. This observation may therefore provide a possible explanation for ineffectiveness of antioxidant therapies and suggests that selective targeting of cRel activation may provide a novel approach for the treatment of stress-related inflammatory vascular disease.
    Type of Publication: Journal article published
    PubMed ID: 23114885
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  • 2
    Keywords: RECEPTOR ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; PROTECTION ; CELL ; Germany ; MODEL ; MODELS ; NF-KAPPA-B ; ACTIVATION ; CELL ACTIVATION ; MECHANISM ; TRANSCRIPTION FACTOR ; mechanisms ; DELETION ; STEPS ; SIGNALING PATHWAYS ; PRODUCT ; SUPERFAMILY ; innate immunity ; Jun ; SOLUBLE RECEPTOR ; immune response ; IMMUNE-RESPONSE ; RECEPTORS ; INITIATION ; inflammation ; ANIMAL-MODELS ; immunoglobulin ; PRODUCTS ; LEADS ; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ; pattern recognition ; CLASS-III REGION ; DIABETIC VASCULOPATHY ; INFLAMMATORY RESPONSES
    Abstract: 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
    Type of Publication: Journal article published
    PubMed ID: 15173891
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  • 3
    Keywords: RECEPTOR ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; MODEL ; PATHWAY ; VITRO ; NEW-YORK ; PROTEIN ; PROTEINS ; MICE ; DISORDER ; RECOGNITION ; WILD-TYPE ; ADHESION ; RECRUITMENT ; ADHESION MOLECULE-1 ; BINDING-PROTEINS ; diabetes ; DIABETIC-RATS ; E-NULL MICE ; FACTOR-KAPPA-B ; GLYCATION END-PRODUCTS ; INTEGRIN ; leukocyte ; peritoneum ; RAGE ; SOLUBLE RECEPTOR ; TISSUE FACTOR ; UROKINASE RECEPTOR
    Abstract: 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 peritonis, 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
    Type of Publication: Journal article published
    PubMed ID: 14623906
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  • 4
    Keywords: RECEPTOR ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; tumor ; CELL ; Germany ; IN-VIVO ; SUPPORT ; NEW-YORK ; TISSUE ; MICE ; LIGAND ; MECHANISM ; CARCINOGENESIS ; KERATINOCYTES ; mechanisms ; SKIN ; BONE-MARROW ; PROGRESSION ; MOUSE SKIN ; skin carcinogenesis ; LIGANDS ; FACTOR-KAPPA-B ; GLYCATION END-PRODUCTS ; inflammation ; signaling ; molecular ; RE ; CANCER DEVELOPMENT ; PHASE ; USA ; BONE ; immunology ; PROMOTES ; MEDICINE ; DOUBLE-EDGED-SWORD
    Abstract: A broad range of experimental and clinical evidence has highlighted the central role of chronic inflammation in promoting tumor development. However, the molecular mechanisms converting a transient inflammatory tissue reaction into a tumor-promoting micro-environment remain largely elusive. We show that mice deficient for the receptor for advanced glycation end-products (RAGE) are resistant to DMBA/TPA-induced skin carcinogenesis and exhibit a severe defect in sustaining inflammation during the promotion phase. Accordingly, RAGE is required for TPA-induced up-regulation of proinflammatory mediators, maintenance of immune cell infiltration, and epidermal hyperplasia. RAGE-dependent up-regulation of its potential ligands S100a8 and S100a9 supports the existence of an S100/RAGE-driven feed-forward loop in chronic inflammation and tumor promotion. Finally, bone marrow chimera experiments revealed that RAGE expression on immune cells, but not keratinocytes or endothelial cells, is essential for TPA-induced dermal infiltration and epidermal hyperplasia. We show that RAGE signaling drives the strength and maintenance of an inflammatory reaction during tumor promotion and provide direct genetic evidence for a novel role for RAGE in linking chronic inflammation and cancer
    Type of Publication: Journal article published
    PubMed ID: 18208974
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  • 5
    Keywords: RECEPTOR ; ENDOTHELIAL-CELLS ; IN-VITRO ; MECHANISM ; BINDING ; AGE ; GLYCATION END-PRODUCTS ; OXIDATIVE STRESS ; Mitochondrial Proteins ; METHYLGLYOXAL MODIFICATION
    Abstract: Methylglyoxal (MG), the major dicarbonyl substrate of the enzyme glyoxalase 1 (GLO1), is a reactive metabolite formed via glycolytic flux. Decreased GLO1 activity in situ has been shown to result in an accumulation of MG and increased formation of advanced glycation endproducts, both of which can accumulate during physiological aging and at an accelerated rate in diabetes and other chronic degenerative diseases. To determine the physiological consequences which result from elevated MG levels and the role of MG and GLO1 in aging, wound healing in young (〈/=12 weeks) and old (〉/=52 weeks) wild-type mice was studied. Old mice were found to have a significantly slower rate of wound healing compared to young mice (74.9 +/- 2.2 vs. 55.4 +/- 1.5% wound closure at day 6; 26% decrease; p 〈 0.0001). This was associated with decreases in GLO1 transcription, expression and activity. The importance of GLO1 was confirmed in mice by inhibition of GLO1. Direct application of MG to the wounds of young mice, decreased wound healing by 24% compared to untreated mice, whereas application of BSA modified minimally by MG had no effect. Treatment of either young or old mice with aminoguanidine, a scavenger of free MG, significantly increased wound closure by 16% (66.8 +/- 1.6 vs. 77.2 +/- 3.1%; p 〈 0.05) and 64% (40.4 +/- 7.9 vs. 66.4 +/- 5.2%; p 〈 0.05), respectively, by day 6. As a result of the aminoguanidine treatment, the overall rate of wound healing in the old mice was restored to the level observed in the young mice. These findings were confirmed in vitro, as MG reduced migration and proliferation of fibroblasts derived from young and old, wild-type mice. The data demonstrate that the balance between MG and age-dependent GLO1 downregulation contributes to delayed wound healing in old mice.
    Type of Publication: Journal article published
    PubMed ID: 23797271
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