Interaction Between NFκB and NFAT Coordinates Cardiac Hypertrophy and Pathological Remodeling

Rationale: Both nuclear factors of activated T cells (NFAT) and nuclear factor-kappa B (NF kappa B) 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 NF kappa B signaling pathways in cardiomyocytes and its role in cardiac hypertrophy and remodeling. Methods and Results: We identified a novel transcriptional regulatory mechanism whereby NF kappa B and NFAT directly interact and synergistically promote transcriptional activation in cardiomyocytes. We show that the p65 subunit of NF kappa B 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 I kappa B kinase beta (IKK beta) 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 NF kappa B with I kappa B alpha M or dominant negative IKK beta 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 approximate to 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 NF kappa B that effectively integrates 2 disparate signaling pathways in promoting cardiac hypertrophy and ventricular remodeling. (Circ Res. 2012;110:1077-1086.)