Abstract 11429: Development of Spontaneous Myocarditis in Nuclear Factor kappa B (NFκB) p50-Deficient Mice: the Emerging Role of NFκB p65 in its Pathogenesis
Background: The transcriptional factor NFκB plays a pivotal role in triggering inflammation and autoimmune responses. We observed spontaneous development of myocarditis in NFκB p50-deficient NOD mice (NODp50-/-); however, the role of NFκB subunits in the pathophysiology of myocarditis remains unclear. The roles and possible function of NFκB subunits were explored in this study.
Methods and Results: NODp50-/- and NODp50+/- control mice were generated by cross breeding NOD mice with B6p50-/- mice over 8 generations. Compared with NODp50+/- (n=4), NODp50-/- (n=5) mice exhibited significant 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). Tissue sections of the hearts from NODp50-/- mice demonstrated marked interstitial fibrosis, infiltration of mononuclear inflammatory cells positive for CD4+ and CD8+ T cells (p<0.05), ten-fold increase in apoptosis of mononuclear cells (p=0.02), and significant upregulation of IL-1β, IL-6, Caspase-1, ICAM-1 mRNA levels (p<0.05). In addition, 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 compared with those of controls. Interestingly, we observed significant upregulation of NFkB p65 mRNA (p=0.01), and strong nuclear staining of p65 in the heart of NODp50-/- mice. The spontaneous development of myocarditis in NODp50-/- mice significantly decreased their survival as compared with NODp50+/- mice: median survival time was 46 days (n=14) and 587.5 days (n=6), respectively (log-rank test, p<0.0001).
Conclusions: The targeted deletion of NFkB p50 caused spontaneous development of myocarditis showing functional deterioration by imparting pro-inflammatory, pro-fibrotic, and pro-apoptotic properties, and resulted in premature death. Upregulation of NFkB p65 in the absence of p50 may promote transcription of pro-inflammatory genes. This study provides new insights into the roles of NFkB p65 in the pathogenesis of myocarditis. Regulation of NFκB function is critical in mediating autoimmune inflammation against myocardium.
- © 2012 by American Heart Association, Inc.