Overexpression of cardiac I-{kappa}B{alpha} prevents endotoxin-induced myocardial dysfunction

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