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  • ENDOTHELIAL-CELLS  (2)
  • 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: ANGIOGENESIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; IN-VITRO ; proliferation ; tumor ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; tumor growth ; VITRO ; VIVO ; DENSITY ; RISK ; GENE ; PROTEIN ; TUMORS ; MICE ; PATIENT ; MECHANISM ; TRANSCRIPTION FACTOR ; TRANSPLANTATION ; mechanisms ; fibroblasts ; ACID ; MALIGNANCIES ; ASSAY ; NUDE-MICE ; MODULATION ; RELATIVE RISK ; signaling ; AGENT ; molecular ; ONCOLOGY ; MOLECULAR-BASIS ; fibroblast ; TUMOR-GROWTH ; DEHYDROGENASE ; mycophenolic acid ; MOLECULAR-MECHANISMS ; analysis ; ASSAYS ; USA ; cancer research ; PROTEIN-KINASE-A ; GLIOBLASTOMA ; microvascular density ; quantitative ; MOFETIL
    Abstract: The relative risk for the development of malignancies following solid organ transplantation seems to be decreased in patients treated with the immunosuppressive agent mycophenolic acid (MPA). However, the molecular mechanisms of the antineoplastic effects of MPA are not completely understood. Here, we report that human endothelial cells and fibroblasts are highly sensitive to MPA treatment. We found that U87 glioblastoma cells were resistant to MPA treatment in vitro. However U87 tumor growth was markedly inhibited in vivo in BALB/c nude mice, suggesting that MPA exerted its antitumor effects via modulation of the tumor microenvironment. Accordingly, microvascular density and pericyte coverage were markedly reduced in MPA-treated tumors in vivo. Using functional in vitro assays, we showed that MPA potently inhibited endothelial cell and fibroblast proliferation, invasion/migration, and endothelial cell tube formation. To identify the genetic participants governing the antiangiogenic and antifibrotic effects of MPA, we performed genome-wide transcriptional analysis in U87, endothelial and fibroblast cells at 6 and 12 h after MPA treatment. Network analysis revealed a critical role for MYC signaling in endothelial cells treated with MPA. Moreover, we found that the antiangiogenic effects of MPA were organized by coordinated communications between MYC and NDRG1, YY1, HIF1A, HDAC2, CDC2, GSK3B, and PRKACB signaling. The regulation of these "hub nodes" was confirmed by real-time quantitative reverse transcription-PCR and protein analysis. The critical involvement of MYC in the antiangiogenic signaling of MPA was further shown by gene knockdown experiments. Together, these data provide a molecular basis for the antiangiogenic and antifibrotic effects of MPA, which warrants further clinical investigations
    Type of Publication: Journal article published
    PubMed ID: 18566237
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