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

Nuclear factor-kappa B (NF-kappaB) is an inducible transcription factor tha t regulates expression of many genes, such as tumor necrosis factor-alpha ( TNF-alpha), which may contribute to myocardial dysfunction. We investigated whether cardiac NF-kappaB activation is involved in the development of myo cardial dysfunction after lipopolysaccharide (LPS) challenge. Mice were int raperitoneally injected with LPS, and the hearts were harvested and assayed for NF-kappaB translocation. After LPS challenge, NF-kappaB activation was detected within 30 min and remained for 8 h. In transgenic mice constituti vely overexpressing a nondegradable form of I-kappaB alpha (I-kappaB alpha DeltaN) in cardiomyocytes, myocardial NF-kappaB translocation was prevented after LPS challenge. Myocytes isolated from these transgenics secreted sig nificantly less TNF-alpha than did wild-type cardiomyocytes after LPS stimu lation. When whole hearts were excised, perfused in a Langendorff preparati on, and challenged with endotoxin, I-kappaB alpha DeltaN transgenic hearts displayed normal cardiac function, whereas profound contractile dysfunction was observed in wild-type hearts. These data indicate that myocardial NF-k appaB translocates within minutes after LPS administration. Inhibition of m yocyte NF-kappaB activation by overexpression of myocyte I-kappaB alpha is sufficient to block cardiac TNF-alpha production and prevent cardiac dysfun ction after LPS challenge.