title: NFATc2 is a necessary mediator of calcineurin-dependent cardiac hypertrophy and heart failure.
abstract: One major intracellular signaling pathway involved in heart failure employs the phosphatase calcineurin and its downstream transcriptional effector nuclear factor of activated T-cells (NFAT). In vivo evidence for the involvement of NFAT factors in heart failure development is still ill defined. Here we reveal that nfatc2 transcripts outnumber those from other nfat genes in the unstimulated heart by severalfold. Transgenic mice with activated calcineurin in the postnatal myocardium crossbred with nfatc2-null mice revealed a significant abrogation of calcineurin-provoked cardiac growth, indicating that NFATc2 plays an important role downstream of calcineurin and validates the original hypothesis that calcineurin mediates myocyte hypertrophy through activation of NFAT transcription factors. In the absence of NFATc2, a clear protection against the geometrical, functional, and molecular deterioration of the myocardium following biomechanical stress was also evident. In contrast, physiological cardiac enlargement in response to voluntary exercise training was not affected in nfatc2-null mice. Combined, these results reveal a major role for the NFATc2 transcription factor in pathological cardiac remodeling and heart failure.
authors.affiliation: Hubrecht Institute and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Meriem
authors.initials: M
authors.lastname: Bourajjaj
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Armand
authors.forename: Paula A
authors.initials: PA
authors.lastname: da Costa Martins
authors.forename: Bart
authors.initials: B
authors.lastname: Weijts
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heeneman
authors.forename: Xander H
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D006332:Cardiomegaly / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000737:chemistry; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms
chemical_list: D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D020033:Protein Isoforms; D019703:Calcineurin