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Am J Physiol Heart Circ Physiol 275: H1084-H1091, 1998;
0363-6135/98 $5.00
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Vol. 275, Issue 3, H1084-H1091, September 1998

Increased levels of myocardial Ikappa B-alpha protein promote tolerance to endotoxin

Brian D. Shames, Daniel R. Meldrum, Craig H. Selzman, Edward J. Pulido, Brian S. Cain, Anirban Banerjee, Alden H. Harken, and Xianzhong Meng

Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80262

Endotoxin [lipopolysaccharide (LPS)] causes tumor necrosis factor-alpha (TNF-alpha )-mediated myocardial contractile depression. Tolerance to the cardiac toxicity of LPS can be induced by a prior exposure to LPS or by pretreatment with glucocorticoids. The mechanisms by which the myocardium acquires tolerance to LPS remain unknown. LPS causes phosphorylation and degradation of inhibitory kappa B-alpha (Ikappa B-alpha ), releasing nuclear factor-kappa B (NF-kappa B) to activate TNF-alpha gene transcription. We hypothesized that LPS induces supranormal synthesis of myocardial Ikappa B-alpha protein and thus renders the myocardium tolerant to subsequent LPS. Rats were challenged with LPS after pretreatment with LPS, dexamethasone, or saline. In saline-pretreated rats, LPS caused a rapid decrease in myocardial Ikappa B-alpha protein levels, activation of NF-kappa B, and increased TNF-alpha production. These events were followed by myocardial contractile depression. After the initial decrease in myocardial Ikappa B-alpha , Ikappa B-alpha protein levels rebounded to a level greater than control levels by 24 h. Dexamethasone pretreatment similarly increased myocardial Ikappa B-alpha protein levels. In rats pretreated with either LPS or dexamethasone, myocardial Ikappa B-alpha protein levels remained similar to control levels after LPS challenge. The preserved level of myocardial Ikappa B-alpha protein was associated with diminished NF-kappa B activation, attenuated myocardial TNF-alpha production, and improved cardiac contractility. We conclude that LPS and dexamethasone upregulate myocardial Ikappa B-alpha protein expression and that an increased level of myocardial Ikappa B-alpha protein may promote cardiac tolerance to LPS by inhibition of NF-kappa B intranuclear translocation and myocardial TNF-alpha production.

nuclear factor-kappa B; tumor necrosis factor-alpha ; cardiac contractility; glucocorticoids; rat


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