دورية
Effect of NF- κ B Inhibition on TNF- α -induced Apoptosis and Downstream Pathways in Cardiomyocytes
| العنوان: | Effect of NF- κ B Inhibition on TNF- α -induced Apoptosis and Downstream Pathways in Cardiomyocytes |
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| المؤلفون: | Bergmann, M. W., Loser, P., Dietz, R., Harsdorf, R. v. |
| المصدر: | Journal of Molecular and Cellular Cardiology; June 2001, Vol. 33 Issue: 6 p1223-1232, 10p |
| مستخلص: | Heart-specific inhibition of survival pathway gp130 was recently shown to sensitize transgenic mice towards stress stimuli, resulting in rapid onset of cardiac dilatation and heart failure. In order to identify further survival pathways we evaluated the role of transcription factor nuclear factor- κ B (NF- κ B) in tumour necrosis factor- α (TNF- α)-induced apoptosis of cardiomyocytes. TNF- α stimulation (10 ng/ml) of both H9c2 cells and primary cardiomyocytes isolated from neonatal Wistar rats resulted in rapid nuclear translocation of NF-κ B complexes. The NF- κ B complexes consisted of rel-proteins p50 and p65, as revealed by supershift analysis. Addition of proteasome inhibitor MG132 or adenoviral expression of a truncated I κ B α (Iκ BΔN) inhibited TNF- α -induced NF- κ B nuclear translocation in a dose-dependent manner. Both neonatal cardiomyocytes and H9c2 cells were resistant to TNF-induced apoptosis. However, specific inhibition of NF-κ B activation by Ad5-I κ B αΔN (MOI=50) or MG132 (5 μ m) increased apoptosis as measured by subG1-assay (H9c2 cells) and annexin V binding/propidium iodide (neonatal cardiomyocytes, FACS-analysis: 7±2% to 26±5% annexin V positive/PI negative), respectively. TUNEL-assay double-stained with anti- α -sarcomeric actin confirmed apoptosis of neonatal cardiomyocytes. Furthermore, caspase-3 activation was increased by 52±7% in neonatal cardiomyocytes after TNF α+Ad5-I κ Bα ΔN compared to TNF α+Ad5-control treatment. Protein levels of hiAP1, hiAP2, x-iAP, bcl-2 and bcl-x(L) were neither downregulated by NF- κ B inhibition nor upregulated by TNF- α stimulation. In summary, cardiomyocytes utilize transcription factor NF- κ B to activate survival factors in the context of TNF-α stimulation. As locally increased levels of TNF- α have been detected in heart failure, NF-κ B activity is essential for cellular homeostasis in the heart. |
| قاعدة البيانات: | Supplemental Index |
Full Text Finder | تدمد: | 00222828 10958584 |
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| DOI: | 10.1006/jmcc.2001.1385 |