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Title: Signaling pathways of tumor necrosis factor A in ventricular myocytes
Authors: Mustapha, Shareef
Issue Date: 1-Mar-1999
Abstract: Elevated levels of serum tumor necrosis factor alpha (TNF$\alpha$) have been reported in patients with cardiac hypertrophy and heart failure. However, the role played by TNF$\alpha$ in the pathogenesis of cardiac disease remains unknown. TNF$\alpha$ may contribute to ventricular dysfunction through the modulation of cardiac muscle gene expression. To test this possibility we transfected neonatal ventricular myocytes with luciferase reporter constructs driven by the $\alpha$-myosin heavy chain ($\alpha$MHC), $\beta$-myosin heavy chain, $\alpha$-cardiac actin, and $\alpha$-skeletal actin genes. TNF$\alpha$ significantly repressed cardiac specific gene expression (p $<$ 0.05). The repression was judged not to be due to the cytotoxicity of TNF$\alpha$ as TNF$\alpha$ did not induce myocyte cell death. The nitric oxide synthase inhibitor, N$\rm\sp{G}$-nitro-L-arginine methyl ester (L-NAME), abrogated the repressive effects of TNF$\alpha$. Furthermore, myocytes expressing an inhibitor of the transcription factor NF$\kappa$B prevented TNF$\alpha$-mediated repression of cardiac specific genes. Our data provide the first indication for the repression of cardiac specific gene expression by TNF$\alpha$ through an NF$\kappa$B and NO dependent pathway. To further delineate the TNF$\alpha$ signal transduction pathway we tested the involvement of the TNF$\alpha$ Receptor Associated Factor 2 (TRAF2) for signaling of NF$\kappa$B. The ring finger and zinc finger domains of TRAF2 are capable of transactivating NF$\kappa$B and are thought to be indispensible for the induction of by NF$\kappa$B by TNF$\alpha$ in some cell types. We tested several structural mutations of TRAF2 in both myocytes and 293 cells. Our data suggests that TRAF2 is essential for TNF$\alpha$ signaling of NF$\kappa$B in 293 cells but not in myocytes. Furthermore, we found that the ring finger domain of TRAF2 is not important for TRAF2 mediated NF$\kappa$B activation in myocytes.
Appears in Collection(s):FGS - Electronic Theses & Dissertations (Public)

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