Key result
Cardiac-specific deletion of p65 in mice reduced NFAT activity by ≈50%, decreased the hypertrophic response to pressure overload, reduced pathological remodeling, and preserved contractile function.
NFAT and NFκB directly interact to synergistically promote cardiac hypertrophy and pathological remodeling, revealing a novel integrated signaling mechanism in heart failure pathogenesis.
Should not change heart failure management; leaves open whether p65-NFAT targeting merits human translation.
RATIONALE: Both nuclear factors of activated T cells (NFAT) and nuclear factor-κB (NFκB) are Rel homology domain (RHD)-containing transcription factors whose independent activities are critically involved in regulating cardiac hypertrophy and failure. OBJECTIVE: To determine the potential functional interaction between NFAT and NFκB signaling pathways in cardiomyocytes and its role in cardiac hypertrophy and remodeling. METHODS AND RESULTS: We identified a novel transcriptional regulatory mechanism whereby NFκB and NFAT directly interact and synergistically promote transcriptional activation in cardiomyocytes. We show that the p65 subunit of NFκB coimmunoprecipitates with NFAT in cardiomyocytes, and this interaction maps to the RHD within p65. Overexpression of the p65-RHD disrupts the association between endogenous p65 and NFATc1, leading to reduced transcriptional activity. Overexpression of IκB kinase β (IKKβ) or p65-RHD causes nuclear translocation of NFATc1, and expression of a constitutively nuclear NFATc1-SA mutant similarly facilitated p65 nuclear translocation. Combined overexpression of p65 and NFATc1 promotes synergistic activation of NFAT transcriptional activity in cardiomyocytes, whereas inhibition of NFκB with IκBαM or dominant negative IKKβ reduces NFAT activity. Importantly, agonist-induced NFAT activation is reduced in p65 null mouse embryonic fibroblasts (MEFs) compared with wild-type MEFs. In vivo, cardiac-specific deletion of p65 using a Cre-loxP system causes a ≈50% reduction in NFAT activity in luciferase reporter mice. Moreover, ablation of p65 in the mouse heart decreases the hypertrophic response after pressure overload stimulation, reduces the degree of pathological remodeling, and preserves contractile function. CONCLUSIONS: Our results suggest a direct interaction between NFAT and NFκB that effectively integrates 2 disparate signaling pathways in promoting cardiac hypertrophy and ventricular remodeling.
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Chen et al. (2012) studied Cardiac hypertrophy and pathological remodeling. Cardiac-specific deletion of p65 vs. Wild-type controls was evaluated on NFAT activity and hypertrophic response after pressure overload. Cardiac-specific deletion of p65 in mice reduced NFAT activity by ≈50%, decreased the hypertrophic response to pressure overload, reduced pathological remodeling, and preserved contractile function.
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