NFATc2 Is a Necessary Mediator of Calcineurin-dependent Cardiac Hypertrophy and Heart Failure

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. 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. Heart failure, or the inability of the heart to meet hemodynamic demands, represents the end stage of various forms of cardiac disease. In the Western world, the prevalence and incidence of heart failure are increasing steadily, and heart failure is now the leading cause of hospitalization in the elderly. The leading cause of heart failure is left ventricular hypertrophy, defined as an increase in heart size without a change in myocyte number, because chronically hypertrophied hearts remodel and dilate (1Ho K.K. Pinsky J.L. Kannel W.B. Levy D. J. Am. Coll. Cardiol. 1993; 22: 6A-13ACrossref PubMed Scopus (1873) Google Scholar, 2Lloyd-Jones D.M. Larson M.G. Leip E.P. Beiser A. D'Agostino R.B. Kannel W.B. Murabito J.M. Vasan R.S. Benjamin E.J. Levy D. Circulation. 2002; 106: 3068-3072Crossref PubMed Scopus (1219) Google Scholar). Conversely, not all forms of cardiac hypertrophy are necessarily pathological, as athletic conditioning can stimulate heart growth without deleterious consequences (3Oakley D. Heart. 2001; 86: 722-726Crossref PubMed Scopus (46) Google Scholar). Hence, a better understanding of the mechanisms underlying pathological versus adaptive hypertrophic growth of the myocardium is key to develop preventative measures and therapeutics for heart failure patients (4Olson E.N. Schneider M.D. Genes Dev. 2003; 17: 1937-1956Crossref PubMed Scopus (338) Google Scholar). Gain- and loss-of-function studies in genetically altered mice and cultured cardiomyocytes have demonstrated the sufficiency and necessity of calcineurin to regulate pathological cardiac hypertrophy (5Molkentin J.D. Lu J.R. Antos C.L. Markham B. Richardson J. Robbins J. Grant S.R. Olson E.N. Cell. 1998; 93: 215-228Abstract Full Text Full Text PDF PubMed Scopus (2205) Google Scholar, 6Antos C.L. McKinsey T.A. Frey N. Kutschke W. McAnally J. Shelton J.M. Richardson J.A. Hill J.A. Olson E.N. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 907-912Crossref PubMed Scopus (414) Google Scholar, 7Bueno O.F. Wilkins B.J. Tymitz K.M. Glascock B.J. Kimball T.F. Lorenz J.N. Molkentin J.D. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4586-4591Crossref PubMed Scopus (218) Google Scholar, 8De Windt L.J. Lim H.W. Bueno O.F. Liang Q. Delling U. Braz J.C. Glascock B.J. Kimball T.F. del Monte F. Hajjar R.J. Molkentin J.D. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3322-3327Crossref PubMed Scopus (179) Google Scholar, 9Hill J.A. Rothermel B. Yoo K.D. Cabuay B. Demetroulis E. Weiss R.M. Kutschke W. Bassel-Duby R. Williams R.S. J. Biol. Chem. 2002; 277: 10251-10255Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 10Rothermel B.A. McKinsey T.A. Vega R.B. Nicol R.L. Mammen P. Yang J. Antos C.L. Shelton J.M. Bassel-Duby R. Olson E.N. Williams R.S. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3328-3333Crossref PubMed Scopus (268) Google Scholar, 11Zou Y. Hiroi Y. Uozumi H. Takimoto E. Toko H. Zhu W. Kudoh S. Mizukami M. Shimoyama M. Shibasaki F. Nagai R. Yazaki Y. Komuro I. Circulation. 2001; 104: 97-101Crossref PubMed Scopus (114) Google Scholar, 12Van Rooij E. Doevendans P.A. Crijns H.J. Heeneman S. Lips D.J. Van Bilsen M. Williams R.S. Olson E.N. Bassel-Duby R. Rothermel B.A. De Windt L.J. Circ. Res. 2004; 94: e18-e26Crossref PubMed Scopus (107) Google Scholar). In contrast, in vivo confirmation about the involvement of its direct downstream transcriptional effectors in the heart is still incompletely resolved. Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT) 2The abbreviations used are: NFATnuclear factor of activated T-cellRTreverse transcriptionMHCmyosin heavy chainWGAwheat germ agglutininLVIDleft ventricular internal diameterFSfractional shorteningBWbody weightHWheart weightTACtransverse aortic. transcription factor family (13Rao A. Luo C. Hogan P.G. Annu. Rev. Immunol. 1997; 15: 707-747Crossref PubMed Scopus (2223) Google Scholar), allowing NFAT to translocate to the nucleus where it cooperates with other transcription factors to regulate calcineurin-responsive target genes. The ventricular cardiomyocyte contains all four calcineurin-sensitive NFATc isoforms, NFATc1 (NFATc), NFATc2 (NFATp), NFATc3 (NFAT4), and NFATc4 (NFAT3) (14van Rooij E. Doevendans P.A. de Theije C.C. Babiker F.A. Molkentin J.D. de Windt L.J. J. Biol. Chem. 2002; 277: 48617-48626Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 15Wilkins B.J. De Windt L.J. Bueno O.F. Braz J.C. Glascock B.J. Kimball T.F. Molkentin J.D. Mol. Cell. Biol. 2002; 22: 7603-7613Crossref PubMed Scopus (217) Google Scholar), and expression of dominant-negative forms of NFAT virtually abolishes calcineurin-mediated hypertrophy in cultured cardiomyocytes (14van Rooij E. Doevendans P.A. de Theije C.C. Babiker F.A. Molkentin J.D. de Windt L.J. J. Biol. Chem. 2002; 277: 48617-48626Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 16Pu W.T. Ma Q. Izumo S. Circ. Res. 2003; 92: 725-731Crossref PubMed Scopus (89) Google Scholar). In vivo, however, nfatc4-null mice harboring a cardiac specific calcineurin transgene did not display a compromise of cardiac hypertrophy and heart failure (15Wilkins B.J. De Windt L.J. Bueno O.F. Braz J.C. Glascock B.J. Kimball T.F. Molkentin J.D. Mol. Cell. Biol. 2002; 22: 7603-7613Crossref PubMed Scopus (217) Google Scholar). nfatc3-null mice are only very partially deficient in their ability to undergo cardiac hypertrophy and display no improvement on hypertrophic marker gene expression or cardiac dysfunction in response to calcineurin activation (15Wilkins B.J. De Windt L.J. Bueno O.F. Braz J.C. Glascock B.J. Kimball T.F. Molkentin J.D. Mol. Cell. Biol. 2002; 22: 7603-7613Crossref PubMed Scopus (217) Google Scholar). Combined, a vast disparity exists between in vivo and in vitro studies concerning the involvement of NFAT factors in cardiac hypertrophy. nuclear factor of activated T-cell reverse transcription myosin heavy chain wheat germ agglutinin left ventricular internal diameter fractional shortening body weight heart weight transverse aortic. Here we provide evidence that NFATc2 mRNA levels are the most abundantly expressed in the heart among all NFAT isoforms. In line, nfatc2-deficient mice harboring a calcineurin transgene or subjected to pressure overload are substantially compromised in their ability to undergo cardiac hypertrophy. Moreover, at 8 weeks after pressure overload, echocardiography indicated marked left ventricular dilation and loss of systolic function in wild-type mice, whereas nfatc2-null mice displayed a prominent reduction in myofiber hypertrophy, preservation of left ventricular geometry and contractility, reduced fibrosis, and a diminished hypertrophic gene program. Remarkably, nfatc2-null mice were not compromised in their ability to undergo athletic cardiac enlargement. Taken together, these findings reveal a main role for NFATc2 downstream of calcineurin signaling in pathological cardiac remodeling. Mice—αMHC-calcineurin transgenic mice, described previously (5Molkentin J.D. Lu J.R. Antos C.L. Markham B. Richardson J. Robbins J. Grant S.R. Olson E.N. Cell. 1998; 93: 215-228Abstract Full Text Full Text PDF PubMed Scopus (2205) Google Scholar) and generously provided by Eric N. Olson, were crossbred with mice harboring a nfatc2 null mutation (17Ranger A.M. Oukka M. Rengarajan J. Glimcher L.H. Immunity. 1998; 9: 627-635Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar) and generously provided by Laurie Glimcher. Aortic Banding and Angiotensin II Infusions—Angiotensin II infusion with Alzet 2002 mini isosmotic pumps was performed as described previously (8De Windt L.J. Lim H.W. Bueno O.F. Liang Q. Delling U. Braz J.C. Glascock B.J. Kimball T.F. del Monte F. Hajjar R.J. Molkentin J.D. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3322-3327Crossref PubMed Scopus (179) Google Scholar). Transverse aortic (TAC) banding or sham surgery was performed in nfatc2+/+ or nfatc2-/- mice. The aorta was subjected to a defined, 27-gauge constriction between the first and second truncus of the aortic arch as described in detail previously (18Rockman H.A. Ross R.S. Harris A.N. Knowlton K.U. Steinhelper M.E. Field L.J. Ross Jr., J. Chien K.R. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 8277-8281Crossref PubMed Scopus (636) Google Scholar). Pressure gradients between the proximal and distal sites of the transverse aortic constriction were determined by Doppler echocardiography (19van Empel V.P. Bertrand A.T. van Oort R.J. van der Nagel R. Engelen M. van Rijen H.V. Doevendans P.A. Crijns H.J. Ackerman S.L. Sluiter W. De Windt L.J. J. Am. Coll. Cardiol. PubMed Scopus Google Scholar) or pressure (18Rockman H.A. Ross R.S. Harris A.N. Knowlton K.U. Steinhelper M.E. Field L.J. Ross Jr., J. Chien K.R. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 8277-8281Crossref PubMed Scopus (636) Google Scholar). remodeling and function were at and 8 weeks after surgery by echocardiography a as described in detail previously (19van Empel V.P. Bertrand A.T. van Oort R.J. van der Nagel R. Engelen M. van Rijen H.V. Doevendans P.A. Crijns H.J. Ackerman S.L. Sluiter W. De Windt L.J. J. Am. Coll. Cardiol. PubMed Scopus Google Scholar). and were in and with and in at and with and or wheat germ agglutinin were a and a for were determined were with the to to and to was One of was used as for reverse II indicated the and was used as described in detail previously Oort R.J. van Rooij E. M. J. van der Nagel R. Doevendans P.A. Schneider M.D. van De Windt L.J. Circulation. PubMed Scopus Google Scholar) and as described in detail in the nfatc2-/- and nfatc2+/+ mice were subjected to voluntary exercise M. Lorenz S. U. Y. S. PubMed Scopus Google Scholar) were in a with an with a with a activated by exercise for and were for the of the exercise results are as were performed and of of by were at the or the were was at a NFATc2 the in the we demonstrated that all four members of the NFAT family in cardiomyocytes (14van Rooij E. Doevendans P.A. de Theije C.C. Babiker F.A. Molkentin J.D. de Windt L.J. J. Biol. Chem. 2002; 277: 48617-48626Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 15Wilkins B.J. De Windt L.J. Bueno O.F. Braz J.C. Glascock B.J. Kimball T.F. Molkentin J.D. Mol. Cell. Biol. 2002; 22: 7603-7613Crossref PubMed Scopus (217) Google Scholar). of the NFAT transcription factor family are expressed as in transcripts S. A. F. J. C. A. C. I. F. E. E. J. Immunol. Google Scholar, Immunity. Full Text PDF PubMed Scopus Google Scholar, R. Y. S. N. J. Immunol. 1998; Google Scholar). the of NFAT transcripts because against NFAT are and to provide NFAT that transcripts for nfatc2 are the most in as and heart nfat genes can have in of nfat in the we their transcripts in hearts from wild-type mice and transgenic mice harboring a of calcineurin of the leading to a hypertrophy response in mice and heart failure at (5Molkentin J.D. Lu J.R. Antos C.L. Markham B. Richardson J. Robbins J. Grant S.R. Olson E.N. Cell. 1998; 93: 215-228Abstract Full Text Full Text PDF PubMed Scopus (2205) Google Scholar, Windt L.J. Lim H.W. D. Molkentin J.D. Circ. Res. 86: PubMed Scopus Google Scholar). The results that nfat for in and and a in NFATc4 with unstimulated hearts these that nfatc2 transcripts outnumber those from other nfat genes in the unstimulated heart by and that and following calcineurin NFATc2 for transcriptional mechanisms calcineurin or pathological hypertrophy in vivo are still ill defined. the of the of nfatc2 transcripts downstream of calcineurin signaling in the postnatal we crossbred nfatc2-null mice with mice. weeks of nfatc2+/+ and nfatc2-/- mice displayed and a of cardiac hypertrophy and In contrast, mice displayed and ventricular and a of the a and Remarkably, mice harboring a null mutation for the nfatc2 gene displayed a reduction in cardiac enlargement a of in with mice. were not between the four and not significant for and mice, from and and wheat germ agglutinin cardiac revealed cardiomyocyte hypertrophy, myocyte of and of and were in whereas mice did not display these a of myofiber hypertrophy, were from nfatc2+/+ and nfatc2-null mice myofiber whereas mice size In contrast, a reduction was in mice that loss of nfatc2 cardiac hypertrophy. the of nfatc2 on hemodynamic all were subjected to and echocardiography at weeks of of are displayed in increase in left ventricular internal diameter and a in systolic were in the mice, whereas these were in and of the of of a of NFAT downstream of calcineurin signaling in the heart Rooij E. Doevendans P.A. Crijns H.J. Heeneman S. Lips D.J. Van Bilsen M. Williams R.S. Olson E.N. Bassel-Duby R. Rothermel B.A. De Windt L.J. Circ. Res. 2004; 94: e18-e26Crossref PubMed Scopus (107) Google Scholar). for were substantially in mice and reduced to in hearts of gene expression is a of pathological hypertrophy and heart failure, and the expression levels of a of genes were for and heavy were substantially nfatc2 In these results that loss of nfatc2 to a significant reduction of all major in the mice display of and and (17Ranger A.M. Oukka M. Rengarajan J. Glimcher L.H. Immunity. 1998; 9: 627-635Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, A.M. J. H. Glimcher Glimcher L.H. J. PubMed Scopus Google Scholar). the that the cardiac was to the because of loss of NFATc2, we of hearts from the for and of nfatc2-null mice no increase in of and NFATc2 was to by expression T.A. R. S. J. 2004; PubMed Scopus Google Scholar). that nfatc2 did not the cardiac by the we in cardiac by with did not a in in cardiac of nfatc2-null mice, transgenic mice, or wild-type mice. results that nfatc2 a in the ability of calcineurin to a myocyte hypertrophy NFATc2 NFATc2 also hypertrophy in response to from transgenic II infusion was nfatc2+/+ and nfatc2-/- mice displayed and In response to nfatc2-null mice still of hypertrophy, was with the response displayed by nfatc2+/+ mice a and banding was a where the aorta was partially for to in that the pressure gradients in all were nfatc2+/+ and nfatc2-/- mice displayed and In response to nfatc2-null mice still of hypertrophy, was with the response displayed by nfatc2+/+ mice. was in and indicating that of nfat was to the cardiac growth response by in response to hemodynamic were not between the and not for nfatc2+/+ and nfatc2-/- sham and nfatc2+/+ and nfatc2-/- and and cardiac did not of in nfatc2+/+ and nfatc2-/- mice. In contrast, cardiomyocyte hypertrophy, myocyte of and of and were in nfatc2+/+ whereas nfatc2-/- mice displayed these in a in response to and were from nfatc2+/+ and nfatc2-/- mice myofiber and whereas nfatc2-/- mice size with nfatc2+/+ mice after surgery and that loss of nfatc2 reduced pressure hypertrophy of gene expression is a of pathological hypertrophy and heart failure, and the expression levels of a of genes were for and heavy were substantially pressure overload in nfatc2-null mice with wild-type these results a clear in the and molecular of pathological cardiac hypertrophy in the absence of NFATc2 Heart of hypertrophy cardiac function and heart failure development in the absence of we performed on nfatc2+/+ and nfatc2-/- mice for 8 on all pressure gradients were 8 no between nfatc2+/+ and nfatc2-/- mice of and not and In contrast, cardiac enlargement was in nfatc2+/+ mice at 8 weeks after whereas nfatc2-/- mice hearts and was by and indicating that nfatc2-/- mice displayed a reduction in cardiac hypertrophy of pressure and no myocyte or of cells in sham Pressure nfatc2-/- hearts myocyte and in with nfatc2+/+ hearts of hearts demonstrated a reduction in in nfatc2-/- hearts with pressure nfatc2+/+ hearts the of nfatc2 on pressure hemodynamic all were subjected to and echocardiography at and 8 weeks after of at and 8 weeks are displayed in weeks after an increase in and and a in systolic were in the nfatc2+/+ mice subjected to pressure overload and in to nfatc2-null 8 weeks after a of the in in and in were in nfatc2+/+ mice, of left ventricular dilation and heart failure and nfatc2-deficient mice displayed a significant reduction of these and and Taken together, these results that nfatc2 not only the heart from pathological hypertrophy also deterioration following biomechanical and in wild-type and nfatc2-null mice 8 weeks after versus versus versus versus versus wild-type after versus versus wild-type after versus versus versus wild-type after versus versus versus wild-type after versus versus versus wild-type after versus versus versus wild-type after versus versus versus wild-type after versus versus wild-type after in a NFATc2 to genetically molecular mechanisms are to pathological versus athletic cardiac because the of cardiac growth not hemodynamic or to heart failure. we voluntary exercise M. Lorenz S. U. Y. S. PubMed Scopus Google Scholar) as a to stimulate physiological cardiac hypertrophy in of nfatc2+/+ and nfatc2-/- mice. weeks of voluntary nfatc2-/- mice were to a cardiac growth response to that in nfatc2+/+ mice as by their and nfatc2+/+ or nfatc2-/- mice did not display evidence of a increase in heart results that signaling is not activated after voluntary that the hypertrophy response was not in nfatc2 null mice. among NFAT in of is the of the NFATc2 in cardiac members of the NFAT family are by four genes and expressed as transcripts in and (13Rao A. Luo C. Hogan P.G. Annu. Rev. Immunol. 1997; 15: 707-747Crossref PubMed Scopus (2223) Google Scholar, S. A. F. J. C. A. C. I. F. E. E. J. Immunol. Google Scholar, Immunity. Full Text PDF PubMed Scopus Google Scholar, R. Y. S. N. J. Immunol. 1998; Google Scholar). we demonstrated the of for all four NFATc in cardiomyocytes (14van Rooij E. Doevendans P.A. de Theije C.C. Babiker F.A. Molkentin J.D. de Windt L.J. J. Biol. Chem. 2002; 277: 48617-48626Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 15Wilkins B.J. De Windt L.J. Bueno O.F. Braz J.C. Glascock B.J. Kimball T.F. Molkentin J.D. Mol. Cell. Biol. 2002; 22: 7603-7613Crossref PubMed Scopus (217) Google Scholar). we the of NFAT because most to the of the levels of NFAT in the heart (15Wilkins B.J. De Windt L.J. Bueno O.F. Braz J.C. Glascock B.J. Kimball T.F. Molkentin J.D. Mol. Cell. Biol. 2002; 22: 7603-7613Crossref PubMed Scopus (217) Google Scholar). Here we that for and are in the nfatc4-null mice harboring a cardiac specific calcineurin transgene did not display a compromise of cardiac hypertrophy and heart failure (15Wilkins B.J. De Windt L.J. Bueno O.F. Braz J.C. Glascock B.J. Kimball T.F. Molkentin J.D. Mol. Cell. Biol. 2002; 22: 7603-7613Crossref PubMed Scopus (217) Google Scholar). In contrast, transcripts for and nfatc2 are most in the with the still at those for nfatc3-null mice are also partially deficient in their ability to undergo cardiac hypertrophy (15Wilkins B.J. De Windt L.J. Bueno O.F. Braz J.C. Glascock B.J. Kimball T.F. Molkentin J.D. Mol. Cell. Biol. 2002; 22: 7603-7613Crossref PubMed Scopus (217) Google Scholar). In we that nfatc2-null mice display abrogation of calcineurin-provoked cardiac growth and a clear protection against the geometrical, functional, and molecular deterioration of the myocardium following hemodynamic The findings for nfatc2 and in the of cardiac remodeling and heart failure downstream of The findings also that mice deficient for nfatc2 and display an of calcineurin-mediated cardiac hypertrophy and heart failure. Conversely, findings with nfatc4-null mice (15Wilkins B.J. De Windt L.J. Bueno O.F. Braz J.C. Glascock B.J. Kimball T.F. Molkentin J.D. Mol. Cell. Biol. 2002; 22: 7603-7613Crossref PubMed Scopus (217) Google Scholar) and the very transcripts levels for and we in the also that nfat have very on hypertrophy (15Wilkins B.J. De Windt L.J. Bueno O.F. Braz J.C. Glascock B.J. Kimball T.F. Molkentin J.D. Mol. Cell. Biol. 2002; 22: 7603-7613Crossref PubMed Scopus (217) Google Scholar). NFAT can have in NFATc1 and NFATc2 are involved in an by transcription of by NFAT through its M. S. H. H. I. E. H. J. PubMed Scopus Google Scholar). that in the heart NFAT for in and and a in NFATc4 mRNA with unstimulated The of the that nfatc2 transcripts outnumber those from other nfat genes in the heart by and that and following calcineurin NFAT to and in it that left ventricular hypertrophy as an response to stress to altered from or or because of loss of after heart and only as the to stress in with the of J. Izumo S. Annu. Rev. 1997; PubMed Scopus Google Scholar). have a of of and the to stress to hemodynamic Rooij E. Doevendans P.A. Crijns H.J. Heeneman S. Lips D.J. Van Bilsen M. Williams R.S. Olson E.N. Bassel-Duby R. Rothermel B.A. De Windt L.J. Circ. Res. 2004; 94: e18-e26Crossref PubMed Scopus (107) Google Scholar, A. H. H.A. Circulation. 2002; PubMed Scopus Google Scholar, C. H.A. J. PubMed Scopus Google Scholar). ventricular hypertrophy is a factor for in J. P. E. D. J. Q. J. B. J. S. Circulation. 2001; 104: PubMed Scopus Google Scholar). the specific transcriptional to a of and in cardiac gene expression that are of cardiac In patients with cardiac failure, improvement to with is with in gene most by a in the mRNA expression of the gene W.T. P. D. J. N. J. 2002; PubMed Scopus Google Scholar). In we a in gene expression in nfatc2-null mice with their wild-type after hemodynamic not the of the and only incompletely the of heart enlargement. In most of pathological hypertrophy to of the a reduction in the hypertrophic response a in the from hypertrophy to heart failure (5Molkentin J.D. Lu J.R. Antos C.L. Markham B. Richardson J. Robbins J. Grant S.R. Olson E.N. Cell. 1998; 93: 215-228Abstract Full Text Full Text PDF PubMed Scopus (2205) Google Scholar, 6Antos C.L. McKinsey T.A. Frey N. Kutschke W. McAnally J. Shelton J.M. Richardson J.A. Hill J.A. Olson E.N. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 907-912Crossref PubMed Scopus (414) Google Scholar, 7Bueno O.F. Wilkins B.J. Tymitz K.M. Glascock B.J. Kimball T.F. Lorenz J.N. Molkentin J.D. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4586-4591Crossref PubMed Scopus (218) Google Scholar, 8De Windt L.J. Lim H.W. Bueno O.F. Liang Q. Delling U. Braz J.C. Glascock B.J. Kimball T.F. del Monte F. Hajjar R.J. Molkentin J.D. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3322-3327Crossref PubMed Scopus (179) Google Scholar, 9Hill J.A. Rothermel B. Yoo K.D. Cabuay B. Demetroulis E. Weiss R.M. Kutschke W. Bassel-Duby R. Williams R.S. J. Biol. Chem. 2002; 277: 10251-10255Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 10Rothermel B.A. McKinsey T.A. Vega R.B. Nicol R.L. Mammen P. Yang J. Antos C.L. Shelton J.M. Bassel-Duby R. Olson E.N. Williams R.S. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 3328-3333Crossref PubMed Scopus (268) Google Scholar, 11Zou Y. Hiroi Y. Uozumi H. Takimoto E. Toko H. Zhu W. Kudoh S. Mizukami M. Shimoyama M. Shibasaki F. Nagai R. Yazaki Y. Komuro I. Circulation. 2001; 104: 97-101Crossref PubMed Scopus (114) Google Scholar, 12Van Rooij E. Doevendans P.A. Crijns H.J. Heeneman S. Lips D.J. Van Bilsen M. Williams R.S. Olson E.N. Bassel-Duby R. Rothermel B.A. De Windt L.J. Circ. Res. 2004; 94: e18-e26Crossref PubMed Scopus (107) Google Scholar). The in and that NFAT transcriptional is activated in a pressure cardiac remodeling and heart failure. results also provide evidence that NFATc2 is not for hypertrophic growth of the heart in response to exercise because heart weight in nfatc2-null mice following voluntary are in with findings in a transgenic harboring an was by pathological hypertrophic remodeling and not by exercise as a to physiological hypertrophy B.J. Bueno O.F. J. D.M. F. Kimball Molkentin J.D. Circ. Res. 2004; 94: PubMed Scopus Google Scholar). cardiac of wild-type and nfatc2 null mice did not in or displayed in we that nfatc2 a in the cardiac myocyte to a hypertrophy we the that to loss of nfatc2 have the cardiac we Combined, these that NFAT transcriptional is a pathway and activated in pathological hypertrophy and heart failure. that NFATc2 activation or its downstream target genes provide a for to forms of pathological cardiac hypertrophy and heart failure. are to Eric Olson and Laurie Glimcher for and and for with