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Am J Physiol Heart Circ Physiol 280: H962-H968, 2001;
0363-6135/01 $5.00
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Vol. 280, Issue 3, H962-H968, March 2001

Overexpression of cardiac I-kappa Balpha prevents endotoxin-induced myocardial dysfunction

Sandra B. Haudek1, Erika Spencer2, Debora D. Bryant1, D. Jean White3, David Maass3, Jureta W. Horton3, Zhijian J. Chen2, and Brett P. Giroir1

1 Department of Pediatrics, 2 Department of Molecular Biology, and 3 Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas 75390

Nuclear factor-kappa B (NF-kappa B) is an inducible transcription factor that regulates expression of many genes, such as tumor necrosis factor-alpha (TNF-alpha ), which may contribute to myocardial dysfunction. We investigated whether cardiac NF-kappa B activation is involved in the development of myocardial dysfunction after lipopolysaccharide (LPS) challenge. Mice were intraperitoneally injected with LPS, and the hearts were harvested and assayed for NF-kappa B translocation. After LPS challenge, NF-kappa B activation was detected within 30 min and remained for 8 h. In transgenic mice constitutively overexpressing a nondegradable form of I-kappa Balpha (I-kappa Balpha Delta N) in cardiomyocytes, myocardial NF-kappa B translocation was prevented after LPS challenge. Myocytes isolated from these transgenics secreted significantly less TNF-alpha than did wild-type cardiomyocytes after LPS stimulation. When whole hearts were excised, perfused in a Langendorff preparation, and challenged with endotoxin, I-kappa Balpha Delta N transgenic hearts displayed normal cardiac function, whereas profound contractile dysfunction was observed in wild-type hearts. These data indicate that myocardial NF-kappa B translocates within minutes after LPS administration. Inhibition of myocyte NF-kappa B activation by overexpression of myocyte I-kappa Balpha is sufficient to block cardiac TNF-alpha production and prevent cardiac dysfunction after LPS challenge.

tumor necrosis factor; transgenic mice; transcription factor; signaling pathways


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