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Published on: December 4, 2018
Interaction between NFκB and NFAT coordinates cardiac hypertrophy and pathological remodeling
Qinghang Liu1, Yi Chen, Mannix Auger-Messier
1Department of Physiology and Biophysics, University of Washington, Seattle, USA.
Circulation Research
|March 10, 2012
Summary
Nuclear factor-kappa B (NFκB) and nuclear factor of activated T cells (NFAT) directly interact to promote cardiac hypertrophy. Inhibiting NFκB reduces NFAT activity, mitigating cardiac remodeling and preserving function.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Signaling
Background:
- Nuclear factors of activated T cells (NFAT) and nuclear factor-κB (NFκB) are transcription factors involved in cardiac hypertrophy and failure.
- Both NFAT and NFκB contain Rel homology domains (RHD).
Purpose of the Study:
- To investigate the functional interaction between NFAT and NFκB signaling pathways in cardiomyocytes.
- To determine the role of this interaction in cardiac hypertrophy and remodeling.
Main Methods:
- Co-immunoprecipitation assays to detect NFAT-NFκB interaction in cardiomyocytes.
- Overexpression studies of NFκB subunits and inhibitors.
- Analysis of NFAT transcriptional activity in response to NFκB manipulation.
- Experiments in p65 null mouse embryonic fibroblasts (MEFs).
- In vivo studies using cardiac-specific p65 deletion in mice with pressure overload.
Main Results:
- NFκB (p65 subunit) and NFAT directly interact in cardiomyocytes, with the interaction mapping to the RHD of p65.
- Overexpression of p65-RHD disrupts p65-NFAT association, reducing transcriptional activity.
- Manipulation of NFκB signaling (e.g., IKKβ, p65) influences NFAT nuclear translocation and activity.
- NFAT activation is reduced in p65 null MEFs.
- Cardiac-specific deletion of p65 in mice significantly reduces NFAT activity.
- Ablation of cardiac p65 attenuates pressure overload-induced cardiac hypertrophy, pathological remodeling, and preserves contractile function.
Conclusions:
- A novel mechanism of direct interaction between NFAT and NFκB integrates these signaling pathways.
- This interaction synergistically promotes cardiac hypertrophy and ventricular remodeling.
- Targeting the NFAT-NFκB interaction may offer therapeutic strategies for heart failure.
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