{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:46:48Z","timestamp":1791215208756,"version":"4.1.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2012,4,13]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Both nuclear factors of activated T cells (NFAT) and nuclear factor-\u03baB (NF\u03baB) are Rel homology domain (RHD)-containing transcription factors whose independent activities are critically involved in regulating cardiac hypertrophy and failure.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>To determine the potential functional interaction between NFAT and NF\u03baB signaling pathways in cardiomyocytes and its role in cardiac hypertrophy and remodeling.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              We identified a novel transcriptional regulatory mechanism whereby NF\u03baB and NFAT directly interact and synergistically promote transcriptional activation in cardiomyocytes. We show that the p65 subunit of NF\u03baB 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\u03baB kinase \u03b2 (IKK\u03b2) 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\u03baB with I\u03baB\u03b1M or dominant negative IKK\u03b2 reduces NFAT activity. Importantly, agonist-induced NFAT activation is reduced in\n              <jats:italic>p65<\/jats:italic>\n              null mouse embryonic fibroblasts (MEFs) compared with wild-type MEFs. In vivo, cardiac-specific deletion of\n              <jats:italic>p65<\/jats:italic>\n              using a Cre-loxP system causes a \u224850% reduction in NFAT activity in luciferase reporter mice. Moreover, ablation of\n              <jats:italic>p65<\/jats:italic>\n              in the mouse heart decreases the hypertrophic response after pressure overload stimulation, reduces the degree of pathological remodeling, and preserves contractile function.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Our results suggest a direct interaction between NFAT and NF\u03baB that effectively integrates 2 disparate signaling pathways in promoting cardiac hypertrophy and ventricular remodeling.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.111.260729","type":"journal-article","created":{"date-parts":[[2012,3,9]],"date-time":"2012-03-09T05:53:07Z","timestamp":1331272387000},"page":"1077-1086","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":159,"title":["Interaction Between NF\u03baB and NFAT Coordinates Cardiac Hypertrophy and Pathological Remodeling"],"prefix":"10.1161","volume":"110","author":[{"given":"Qinghang","family":"Liu","sequence":"first","affiliation":[{"name":"From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (Q.L., Y.C.); and the Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital (M.A.-M., J.D.M.), and the Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (Q.L., Y.C.); and the Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital (M.A.-M., J.D.M.), and the Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mannix","family":"Auger-Messier","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (Q.L., Y.C.); and the Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital (M.A.-M., J.D.M.), and the Howard Hughes Medical Institute, Cincinnati, OH (J.D.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"From the Department of Physiology and Biophysics, University of Washington, Seattle, WA (Q.L., Y.C.); and the Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital (M.A.-M., J.D.M.), and the 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