Abstract 10133: Targeted Disruption of p50 Subunit of Nuclear Factor kappa B (NFκB) Leads to Spontaneous Myocarditis in Mice
Background: A key transcription factor NFκB orchestrates pro-inflammatory and autoimmune responses, and thus interference with its activation has been believed to represent new therapeutic approaches for inflammatory myocardial injury. In this study we explored the mechanism of myocarditis, which spontaneously developed in NOD mice lacking p50 subunit of NFκB.
Methods and Results: NOD mice and B6p50-/- mice were cross-bred for over 8 generations to produce NODp50-/- (n=5) and NODp50+/- control mice (n=4). Increase in heart weight to body weight ratio (p<0.05) and decrease in left ventricular ejection fraction (56.7±3.4% vs 67.1±1.9%, p=0.03) were observed in NODp50-/- mice. Tissue sections of the heart from NODp50-/- mice showed marked infiltration of mononuclear inflammatory cells (23.1±2.8 % of total surface area), while NODp50+/- control mice showed no signs of inflammation. The number of infiltrating cells positive for CD4 (p=0.02) and CD8 (p=0.02) cells were significantly higher in NODp50-/- mice than in controls. In addition, there were significantly more apoptotic (TUNEL positive) nuclei in the hearts of NODp50-/- mice compared to those of controls (132±30 cells vs 13.3±8.3 cells, p=0.02). Flow cytometric analysis of serum cytokine levels for IL-6 (p=0.01), MCP-1 (p=0.01) and TNFα (p=0.01) were significantly higher in NODp50-/- mice. The mRNA levels in the heart for pro-inflammatory cytokines IL-1β (33 fold, p=0.01), IL-6 (33 fold, p=0.01), and Caspase 1 (6.7 fold, p=0.01) were significantly up regulated in NODp50-/- mice. Interestingly, we observed significant up regulation of p65 mRNA (p=0.01) in the heart of NODp50-/- mice.
Conclusions: This is the first report of the spontaneous development of myocarditis in p50-deficient NOD mice. Regulation of NFκB function is critical in the development of myocarditis. Enhancement of p65 may play, at least in part, an important role in the inflammation mediating autoimmune response against myocardium.
- © 2011 by American Heart Association, Inc.