Tissue factor (TF), a main initiator of clotting, is upregulated in vasculopathy, We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT, receptor blockade inhibits TF expression in a model of ...
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Tissue factor (TF), a main initiator of clotting, is upregulated in vasculopathy, We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT, receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left ventricular hypertrophy with focal areas of necrosis, and die at age 7 weeks. Plasma and cardiac ANG IT was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophpy (p < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-KB (NF-kappa B) and activator protein-1 CAP-I) activation, and c-fos expression in dTGR hearts. NF-kappa B subunit p65 and TF expression was Increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment. To analyze the mechanism of TF transcription, we then transfected human coronary artery smooth muscle cells and Chinese hamster ovary cells overexpressing the AT, receptor with plasmids containing the human TF promoter and the luciferase reporter gene. ANG II induced the full-length TF promoter in both transfected cell Lines. TF transcription was abolished by AT, receptor blockade. Deletion of both AP-1 and NF-kappa B sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows atl aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of BT, receptor blockade in this model are mediated via the inhibition of NF-kappa B and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and microin
Glioblastoma multiforme (GBM) is the most malignant astroglial-derived rumors which has the propensity to aggressively infiltrate normal regions of the brain surrounding the tumor. The interaction of tumor cells with ...
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Glioblastoma multiforme (GBM) is the most malignant astroglial-derived rumors which has the propensity to aggressively infiltrate normal regions of the brain surrounding the tumor. The interaction of tumor cells with the extracellular matrix (ECM) is an integral step in the process of tumorigenesis and may play a role in the local invasion of the GBM cells. Our study investigated the role of the nuclear transcription factor NF-kappa B on GBM integrin expression and cell attachment. Our results show that treatment of GBM cell lines, SNB-19 and T98G with PMA, an inducer of NF-kappa B, increased the expression of fibronectin and vitronectin genes. Accordingly, ectopic over-expression of NF kappa B subunits in GBM cells elevated the levels of fibronectin gene expression, providing direct Evidence for a regulatory role for NF-kappa B in ECM protein production. Cell attachment to the ECM proteins including fibronectin, vitronectin and laminin was increased in GBM and normal astrocytic cells. Interestingly, treatment of cells with PMA augmented attachment of SNB-19 and T98G cells to fibronectin and vitronectin, however it had no effect on attachment of normal astrocytes. Addition of the tripeptide arginine-glycine-asparatic acid (RGD), the recognition site for many integrins, significantly inhibited SNB-19 and T98G cell attachment to fibronectin and vitronectin. Finally, activation of NF kappa B upon treatment of SNB cells with PMA led to an increase in the levels of mRNA for the beta 3 and the alpha v integrin subunits. Collectively, these data demonstrate a possible role for NF-kappa B in glioma cell attachment. J. Cell. Physiol. 184:214-221, 2000. (C) 2000 Wiley-Liss, Inc.
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