FOXO3a gene transfer prevented IGF- and stretch-induced hypertrophy in vitro and significantly reduced cardiomyocyte size in vivo by activating an atrogene transcriptional program.
Although signaling mechanisms inducing cardiac hypertrophy have been extensively studied, little is known about the mechanisms that reverse cardiac hypertrophy. Here, we describe the existence of a similar Akt/forkhead signaling axis in cardiac myocytes in vitro and in vivo, which is regulated by insulin, insulin-like growth factor (IGF), stretch, pressure overload, and angiotensin II stimulation. FOXO3a gene transfer prevented both IGF and stretch-induced hypertrophy in rat neonatal cardiac myocyte cultures in vitro. Transduction with FOXO3a also caused a significant reduction in cardiomyocyte size in mouse hearts in vivo. Akt/FOXO signaling regulated the expression of multiple atrophy-related genes “atrogenes,” including the ubiquitin ligase atrogin-1 (MAFbx). In cardiac myocyte cultures, transduction with constitutively active Akt or treatment with IGF suppressed atrogin-1 mRNA expression, whereas transduction with FOXO3a stimulated its expression. FOXO3a transduction activated the atrogin-1 promoter in both cultured myocytes and mouse heart. Thus, in cardiomyocytes, as in skeletal muscle, FOXO3a activates an atrogene transcriptional program, which retards or prevents hypertrophy and is down-regulated by multiple physiological and pathological stimuli of myocyte growth. Although signaling mechanisms inducing cardiac hypertrophy have been extensively studied, little is known about the mechanisms that reverse cardiac hypertrophy. Here, we describe the existence of a similar Akt/forkhead signaling axis in cardiac myocytes in vitro and in vivo, which is regulated by insulin, insulin-like growth factor (IGF), stretch, pressure overload, and angiotensin II stimulation. FOXO3a gene transfer prevented both IGF and stretch-induced hypertrophy in rat neonatal cardiac myocyte cultures in vitro. Transduction with FOXO3a also caused a significant reduction in cardiomyocyte size in mouse hearts in vivo. Akt/FOXO signaling regulated the expression of multiple atrophy-related genes “atrogenes,” including the ubiquitin ligase atrogin-1 (MAFbx). In cardiac myocyte cultures, transduction with constitutively active Akt or treatment with IGF suppressed atrogin-1 mRNA expression, whereas transduction with FOXO3a stimulated its expression. FOXO3a transduction activated the atrogin-1 promoter in both cultured myocytes and mouse heart. Thus, in cardiomyocytes, as in skeletal muscle, FOXO3a activates an atrogene transcriptional program, which retards or prevents hypertrophy and is down-regulated by multiple physiological and pathological stimuli of myocyte growth. Cardiac hypertrophy occurs during normal physiological growth of the organism and as an adaptive response to pressure or volume stress, mutations in cardiac proteins, or metabolic perturbations (1Hunter J.J. Chien K.R. N. Engl. J. Med. 1999; 341: 1276-1283Crossref PubMed Scopus (740) Google Scholar). Hypertrophy is characterized by an increase in cell size, enhanced protein synthesis and, in some cases, reorganization of the sarcomere. In pathological hypertrophy, the increase in cardiac myocyte size is thought to be a compensatory mechanism to diminish wall stresses that result from hypertension, valvular heart disease, or myocardial infarction. Ventricular hypertrophy is associated with a significantly increased risk of heart failure and malignant arrhythmias (2Levy D. Garrison R.J. Savage D.D. Kannel W.B. Castelli W.P. N. Engl. J. Med. 1990; 322: 1561-1566Crossref PubMed Scopus (4854) Google Scholar). Multiple signaling pathways contribute to the hypertrophic phenotype (3Sugden P.H. Circ. Res. 2003; 93: 1179-1192Crossref PubMed Scopus (97) Google Scholar, 4Wilkins B.J. Molkentin J.D. J. Physiol. 2002; 541: 1-8Crossref PubMed Scopus (146) Google Scholar). A number of studies have shown that the serine-threonine kinase Akt (protein kinase B) is an important regulator of myocyte growth (5Pham F.H. Cole S.M. Clerk A. Adv. Enzyme Regul. 2001; 41: 73-86Crossref PubMed Scopus (18) Google Scholar) and survival (6Fujio Y. Nguyen T. Wencker D. Kitsis R.N. Walsh K. Circulation. 2000; 101: 660-667Crossref PubMed Scopus (735) Google Scholar). Many stimuli activate Akt including the growth factors insulin and IGF 1The abbreviations used are: IGF, insulin-like growth factor; NRVMs, neonatal rat ventricular myocytes; DMEM, Dulbecco's modified Eagle's medium; WT-FOXO3a, wild-type FOXO3a; GSK3β, glycogen synthase kinase 3β; FBS, fetal bovine serum; pfu, plaque forming unit(s); GFP, green fluorescent protein; PBS, phosphate-buffered saline; DAPI, 4,6-diamidino-2-phenylindole; QRT, quantitative reverse transcriptase; Ct, crossing threshold; PI, phosphatidylinositol; CIRKO, cardiac insulin receptor knock-out; Igfbp5, insulin-like growth factor binding protein 5. (7Shiojima I. Yefremashvili M. Luo Z. Kureishi Y. Takahashi A. Tao J. Rosenzweig A. Kahn C.R. Abel E.D. Walsh K. J. Biol. Chem. 2002; 277: 37670-37677Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar), angiotensin II (8Saad M.J. Velloso L.A. Carvalho C.R. Biochem. J. 1995; 310: 741-744Crossref PubMed Scopus (68) Google Scholar), and mechanical stress (9Petroff M.G. Kim S.H. Pepe S. Dessy C. Marban E. Balligand J.L. Sollott S.J. Nat. Cell Biol. 2001; 3: 867-873Crossref PubMed Scopus (265) Google Scholar). Constitutive overexpression of Akt in transgenic mice can lead to enhanced contractility (10Condorelli G. Drusco A. Stassi G. Bellacosa A. Roncarati R. Iaccarino G. Russo M.A. Gu Y. Dalton N. Chung C. Latronico M.V. Napoli C. Sadoshima J. Croce C.M. Ross Jr., J. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 12333-12338Crossref PubMed Scopus (402) Google Scholar), cytoprotection (11Shiraishi I. Melendez J. Ahn Y. Skavdahl M. Murphy E. Welch S. Schaefer E. Walsh K. Rosenzweig A. Torella D. Nurzynska D. Kajstura J. Leri A. Anversa P. Sussman M.A. Circ. Res. 2004; 94: 884-891Crossref PubMed Scopus (181) Google Scholar), and pathological cardiac hypertrophy (12Matsui T. Li L. Wu J.C. Cook S.A. Nagoshi T. Picard M.H. Liao R. Rosenzweig A. J. Biol. Chem. 2002; 277: 22896-22901Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, 13Shioi T. McMullen J.R. Kang P.M. Douglas P.S. Obata T. Franke T.F. Cantley L.C. Izumo S. Mol. Cell. Biol. 2002; 22: 2799-2809Crossref PubMed Scopus (447) Google Scholar). Akt signaling is also an important determinant of physiological heart growth and coordinates heart size with body size as the nutritional status of the organism varies (7Shiojima I. Yefremashvili M. Luo Z. Kureishi Y. Takahashi A. Tao J. Rosenzweig A. Kahn C.R. Abel E.D. Walsh K. J. Biol. Chem. 2002; 277: 37670-37677Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). The growth factor/Akt signaling pathway up-regulates protein expression through mechanisms involving the activation of the mammalian target of rapamycin (13Shioi T. McMullen J.R. Kang P.M. Douglas P.S. Obata T. Franke T.F. Cantley L.C. Izumo S. Mol. Cell. Biol. 2002; 22: 2799-2809Crossref PubMed Scopus (447) Google Scholar), eukaryotic initiation factor 4E-binding proteins (14Thomas G. Hall M.N. Curr. Opin. Cell Biol. 1997; 9: 782-787Crossref PubMed Scopus (414) Google Scholar), p70S6k (7Shiojima I. Yefremashvili M. Luo Z. Kureishi Y. Takahashi A. Tao J. Rosenzweig A. Kahn C.R. Abel E.D. Walsh K. J. Biol. Chem. 2002; 277: 37670-37677Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar), and the inhibition of GSK3β (15Haq S. Choukroun G. Kang Z.B. Ranu H. Matsui T. Rosenzweig A. Molkentin J.D. Alessandrini A. Woodgett J. Hajjar R. Michael A. Force T. J. Cell Biol. 2000; 151: 117-130Crossref PubMed Scopus (335) Google Scholar). Relatively little is known about the mechanisms that negatively regulate the hypertrophic phenotype. Hearts undergo a reduction in size in response to a number of environmental parameters including decreased nutritional input and decreased load. For example, patients with anorexia nervosa have markedly reduced heart size (16de Simone G. Scalfi L. Galderisi M. Celentano A. Di Biase G. Tammaro P. Garofalo M. Mureddu G.F. de Divitiis O. Contaldo J. PubMed Google Scholar), and reduction in patients is associated with reduced heart size in the of in pressure or parameters E. K. Y. A. M. J. PubMed Scopus Google Scholar). size also ventricular A. Circulation. PubMed Scopus Google Scholar) and by in volume and pressure Circ. Res. PubMed Scopus Google Scholar, R.J. J.C. Circ. Res. PubMed Scopus (97) Google Scholar). in cardiac also heart C. T. S. H. Nat. Med. PubMed Scopus Google Scholar, P. S. J. Li S. H. Circulation. 2003; PubMed Scopus Google Scholar). The of factors a target of of FOXO3a and which by Akt M.J. S. PubMed Scopus Google Scholar, A. A. M.J. P. M.J. J. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). by Akt to and the inhibition of the transcriptional factors have been in including and survival D. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, C. H. Kim J. Walsh K. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). factors have also been shown to in skeletal D. Y. M. Mol. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, M. C. A. C. E. Picard A. Walsh K. S. S.H. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). the and of factors in cardiac myocyte been describe a of that regulated in of skeletal S.H. A. M. J. J. 2004; PubMed Scopus Google Scholar, S.H. A. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, S.H. M. J. 2002; PubMed Scopus Google Scholar, A. C. J. Physiol. 2004; PubMed Scopus Google Scholar). In skeletal muscle, the atrogene to as atrogin-1 or is regulated by the growth factor/Akt signaling axis through transcriptional by factors D. Y. M. Mol. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, M. C. A. C. E. Picard A. Walsh K. S. S.H. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, A. C. J. Physiol. 2004; PubMed Scopus Google Scholar). of the of an in as a of an S.H. A. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, S.H. M. J. 2002; PubMed Scopus Google Scholar, A. C. J. Physiol. 2004; PubMed Scopus Google Scholar, E. S. L. E. K. 2001; PubMed Scopus Google Scholar). ubiquitin that ubiquitin to proteins, J. Wu Y. J. C. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, N. L. J.J. P. C. S.J. M. 2002; PubMed Scopus Google Scholar, C. P. K. L. M. S.J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). Li C. H. R. C. J. 2004; PubMed Scopus Google Scholar) that atrogin-1 cardiac hypertrophy. the that the of factors in cardiac myocytes and regulated by the growth factor/Akt signaling axis in vitro and in vivo. also that an atrogene transcriptional and that to regulate myocyte size from multiple of cardiac hypertrophy. Cell and rat ventricular myocytes from neonatal by a of the as C.M. A. Takahashi N. J. 1995; PubMed Scopus Google Scholar). in Dulbecco's modified Eagle's with fetal bovine and or and or transduction the to by of the as been J. D. O. J. Cell Sci. PubMed Google Scholar). a in a and to a of a of in a of to a of the with a of to as from from from insulin from and angiotensin II from wild-type FOXO3a and a constitutively active FOXO3a C. H. Kim J. Walsh K. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). and have been M. C. A. C. E. Picard A. Walsh K. S. S.H. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). and constitutively active of Akt with the as Y. K. T. Y. J.R. Walsh K. Mol. Cell. Biol. 1999; PubMed Scopus (188) Google Scholar). The Akt and The constitutively active Akt the to the of the wild-type Akt that the protein to the a GSK3β and to and the constitutively active of GSK3β, the to C. A. T. Kureishi Y. M. Jr., Walsh K. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). in and by as For myocyte cultures with a of of cultures with an the by the or which the gene from the promoter D. K. H. C. A. P. Walsh K. 1997; PubMed Scopus Google Scholar). the transduction neonatal cardiac myocytes cultured in and with the as an with and with with PBS, in and with a of by with a of in The in PBS, the and the a a of and Transduction the expression of in the of or by of the C. A. T. Kureishi Y. M. Jr., Walsh K. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). in with in of and of to cell and the protein the protein of protein by and to a The and and with the a in the with bovine The the in the by or the used in and or or used a of and from by with reverse in an as a to the and reverse and the of the from by and the genes to used as rat atrogin-1 reverse and reverse rat and reverse to be with a and of and that multiple be of the in and the crossing For of a and a reverse to the of a in the of in gene expression the in vitro rat neonatal cardiac myocytes cultured in and with as in with the atrogin-1 and to a by the The have been M. C. A. C. E. Picard A. Walsh K. S. S.H. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Cell by a cell a with a as by the For in of with of atrogin-1 M. C. A. C. E. Picard A. Walsh K. S. S.H. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar) and of the and Hearts the ventricular wall and in cell promoter and atrogin-1 to of in neonatal cardiac myocytes cultured Hypertrophy by with or insulin with growth with the with and the with to cell For neonatal rat ventricular cardiac myocytes with the and the of the green fluorescent and of cell size mice and as (7Shiojima I. Yefremashvili M. Luo Z. Kureishi Y. Takahashi A. Tao J. Rosenzweig A. Kahn C.R. Abel E.D. Walsh K. J. Biol. Chem. 2002; 277: 37670-37677Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). mice with insulin, of body mice a constitutively active of in the heart (6Fujio Y. Nguyen T. Wencker D. Kitsis R.N. Walsh K. Circulation. 2000; 101: 660-667Crossref PubMed Scopus (735) Google Scholar) by crossing mice with mice Z. Circ. Res. PubMed Scopus Google Scholar), which the of a and K. mice H. J.L. M.J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). mice normal as R. N. M. S. I. M. K. S. K. T. Walsh K. Nat. Med. 2004; PubMed Scopus Google Scholar). with and the hearts and in in cell with of and studies by the and of of In of Cell and in transfer by of of or the ventricular wall of wild-type hearts and in to expression, used to cell and with FOXO3a mouse heart and cell size with of and of from hearts of transgenic mice promoter in the to the used to by and the to and by and to transgenic mice hearts the of the the of the and the of the the a the of by the from of in the with by as the number of A to be of in Cardiac in factors have been in cardiac we the growth signaling axis is in cell shown in of cardiac myocytes with or increased the of FOXO3a and In a of of cardiac myocytes with insulin to in the of Akt and the factors treatment with both Akt and factor of the of factors its FOXO3a is regulated by Akt myocytes with constitutively active or Akt and or and in and is constitutively active be by A. A. M.J. P. M.J. J. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, T. Kim L.A. Walsh K. Mol. Cell. Biol. 2002; 22: PubMed Scopus Google Scholar). of and in of FOXO3a from the whereas of and caused a of FOXO3a In the of by transduction with or that factors in cardiac myocytes and that can be regulated by the signaling FOXO3a of the of that overexpression of FOXO3a rat neonatal ventricular myocytes with or and the of Akt by shown in transduction with or increased the of Akt of of in in mouse to FOXO3a in the heart in Cardiac insulin receptor mice have a heart phenotype of Akt signaling (7Shiojima I. Yefremashvili M. Luo Z. Kureishi Y. Takahashi A. Tao J. Rosenzweig A. Kahn C.R. Abel E.D. Walsh K. J. Biol. Chem. 2002; 277: 37670-37677Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). with wild-type mice mice reduced of Akt and FOXO3a In of insulin in wild-type mice to in the of FOXO3a and that the FOXO3a of Akt we in transgenic mouse hearts that a constitutively active of In the and activation of Akt by by an increase in the of mice that the of FOXO3a in the heart. that the growth signaling axis factor in vivo. of of II cardiac myocytes can contribute to the increase in cardiac during pathological hypertrophy. with II in we a significant increase in Akt that by enhanced of FOXO3a activation of the signaling axis of pathological hypertrophy in vivo, a pressure of of hearts a significant activation of Akt that in an increase in of FOXO3a that the of the signaling axis can be by of pathological hypertrophy both in vitro and in vivo. FOXO3a in to and Cardiac in the of FOXO3a cardiac myocyte size in neonatal rat ventricular myocytes with in the or of with a increase in cardiac myocyte size with whereas growth factor to a significant in cell The increase in myocyte size by transduction with Transduction with WT-FOXO3a, which can be by growth factor the hypertrophic of myocyte Cardiac been shown to hypertrophy through receptor activation of Akt signaling (9Petroff M.G. Kim S.H. Pepe S. Dessy C. Marban E. Balligand J.L. Sollott S.J. Nat. Cell Biol. 2001; 3: 867-873Crossref PubMed Scopus (265) Google Scholar, M. L. A. E. R. S. M. C. G. L. G. G. Nat. Med. 2003; 9: PubMed Scopus Google Scholar). FOXO3a hypertrophy by myocytes and to an increase in both Akt and FOXO3a which by an increase in cardiac myocyte size The increase in cardiac cell size with whereas transduction with the hypertrophic FOXO3a Cardiac in or in the wall of wild-type the and a of cell size in of the by FOXO3a or by the of Cell by with Transduction with FOXO3a caused a significant in myocyte size with the that The in cell size by increased in of in Cardiac in skeletal as a of genes that regulated during of S.H. A. M. J. J. 2004; PubMed Scopus Google Scholar, S.H. M. J. 2002; PubMed Scopus Google Scholar, A. C. J. Physiol. 2004; PubMed Scopus Google Scholar). signaling through the IGF pathway both skeletal and cardiac cell size, we similar in in by transgenic mice that a constitutively active of Akt the of a by a increase in to body and the of expression to the of cardiac hypertrophy by to the of of Akt expression suppressed during Akt whereas Akt associated with a activation of atrogin-1 to in skeletal that suppressed Akt and Akt in cardiac myocytes and factor the expression of insulin-like growth factor binding protein stimulated by Akt and reduced Akt significantly regulated in transgenic factor growth factor binding protein in a atrogene in atrogin-1 and in cultured cardiac to an increase in atrogin-1 expression that by the of insulin in the insulin treatment a in the expression of ligase E. S. L. E. K. 2001; PubMed Scopus Google Scholar), which the In treatment expression, whereas transduction with to an increase in expression with also atrogin-1 expression and transduction with or to a increase in expression The FOXO3a inducing atrogin-1 wild-type the of the atrogin-1 gene in cultured myocytes a a of the promoter M. C. A. C. E. Picard A. Walsh K. S. S.H. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar) with the by with the atrogin-1 Transduction with a constitutively active of suppressed atrogin-1 promoter whereas a of activated the Transduction with the FOXO3a to a of atrogin-1 promoter The the promoter the wild-type FOXO3a In and constitutively active or GSK3β promoter the of the the atrogin-1 promoter with WT-FOXO3a, or the ventricular wall of mouse hearts gene transfer to increased the in of the atrogin-1 promoter whereas the increased atrogin-1 promoter ventricular hypertrophy is characterized by an increase in cardiac myocyte Cardiac myocyte size is by the of protein synthesis and In we characterized the factors and describe in and cell size in cardiac and in myocytes and regulated by in response to multiple hypertrophic we that of factors as a regulator of cardiac myocyte size that the expression of an atrogene The growth signaling axis is a regulator of heart of the receptor J.R. T. L. O. E. M. S. J. L. Kang P.M. Izumo S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), M.A. I. R. H. T. E. A. T. J. R. G. L. J.L. Kahn C.R. Izumo S. P.H. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), or Akt (10Condorelli G. Drusco A. Stassi G. Bellacosa A. Roncarati R. Iaccarino G. Russo M.A. Gu Y. Dalton N. Chung C. Latronico M.V. Napoli C. Sadoshima J. Croce C.M. Ross Jr., J. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 12333-12338Crossref PubMed Scopus (402) Google Scholar, T. Li L. Wu J.C. Cook S.A. Nagoshi T. Picard M.H. Liao R. Rosenzweig A. J. Biol. Chem. 2002; 277: 22896-22901Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, 13Shioi T. McMullen J.R. Kang P.M. Douglas P.S. Obata T. Franke T.F. Cantley L.C. Izumo S. Mol. Cell. Biol. 2002; 22: 2799-2809Crossref PubMed Scopus (447) Google Scholar) to a significant increase in heart in mice the insulin receptor in cardiac myocytes a heart phenotype in to signaling (7Shiojima I. Yefremashvili M. Luo Z. Kureishi Y. Takahashi A. Tao J. Rosenzweig A. Kahn C.R. Abel E.D. Walsh K. J. Biol. Chem. 2002; 277: 37670-37677Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). of signaling to be a of physiological heart growth mice a of in cardiac myocytes hypertrophy in response to pressure J.R. T. L. O. Kang P.M. Izumo S. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). overexpression of Akt in cardiac myocytes in lead to cell in the of reorganization or activation of cardiac which associated with pathological hypertrophy (7Shiojima I. Yefremashvili M. Luo Z. Kureishi Y. Takahashi A. Tao J. Rosenzweig A. Kahn C.R. Abel E.D. Walsh K. J. Biol. Chem. 2002; 277: 37670-37677Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). that signaling also to the pathological hypertrophic is activated by pressure S. I. Walsh K. J.R. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) and overexpression of Akt is to pathological hypertrophy in transgenic mice (12Matsui T. Li L. Wu J.C. Cook S.A. Nagoshi T. Picard M.H. Liao R. Rosenzweig A. J. Biol. Chem. 2002; 277: 22896-22901Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, 13Shioi T. McMullen J.R. Kang P.M. Douglas P.S. Obata T. Franke T.F. Cantley L.C. Izumo S. Mol. Cell. Biol. 2002; 22: 2799-2809Crossref PubMed Scopus (447) Google Scholar). that the of by signaling is an important determinant of cardiac myocyte size as is in skeletal S.H. M. J. 2002; PubMed Scopus Google Scholar). Multiple including growth stretch, angiotensin and pressure overload, lead to the of that diminish as (7Shiojima I. Yefremashvili M. Luo Z. Kureishi Y. Takahashi A. Tao J. Rosenzweig A. Kahn C.R. Abel E.D. Walsh K. J. Biol. Chem. 2002; 277: 37670-37677Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar), to the and activate genes that associated with an S.H. A. M. J. J. 2004; PubMed Scopus Google Scholar, N. Engl. J. Med. PubMed Scopus Google Scholar). In to the that factors regulated of Akt signaling in cardiac also that overexpression of FOXO3a the of that FOXO3a can the Akt signaling pathway in cardiac myocytes in a that to the increase in in to a that that overexpression Akt signaling in H. R. M.H. PubMed Scopus Google Scholar). a number of transcriptional of Akt/FOXO signaling in the heart that be in the of cardiac proteins the factor the ubiquitin and which target proteins protein a and gene and in of skeletal M. C. A. C. E. Picard A. Walsh K. S. S.H. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, S.H. M. J. 2002; PubMed Scopus Google Scholar, A. C. J. Physiol. 2004; PubMed Scopus Google Scholar). is in skeletal during S.H. A. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar), D.D. J. Biochem. Cell Biol. 2003; PubMed Scopus Google Scholar), failure S.H. A. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar), S.H. A. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar), and E. S. L. E. K. 2001; PubMed Scopus Google Scholar). the atrogin-1 gene during E. S. L. E. K. 2001; PubMed Scopus Google Scholar) and both ubiquitin by and in skeletal E. S. L. E. K. 2001; PubMed Scopus Google Scholar). the of the factor which in with to increase the of ubiquitin S. M. M. N. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), the of the atrogin-1 and ubiquitin is a Although have a in is markedly in skeletal of and be in the of during C. S. C. D. L. D. M. Biochem. J. 2001; PubMed Scopus Google Scholar). the response to E. A. H. J. 2002; PubMed Scopus Google Scholar) and is down-regulated in of skeletal S.H. A. M. J. J. 2004; PubMed Scopus Google Scholar). from transgenic mice that be a transcriptional target of Y. S. M. Y. J. T. K. T. J. H. I. O. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). that the Akt/FOXO signaling axis transcriptional in the heart that to the transcriptional that in skeletal during that similar mechanisms the reduction in cell size in both Li C. H. R. C. J. 2004; PubMed Scopus Google Scholar) that atrogin-1 is in heart and cardiac hypertrophy by been that hypertrophy by IGF and occurs signaling pathways B.J. S.A. J. Molkentin J.D. Circ. Res. 2004; 94: PubMed Scopus Google Scholar). and the of Li C. H. R. C. J. 2004; PubMed Scopus Google Scholar) that atrogin-1 as a regulator of myocyte hypertrophy that signaling In a in signaling lead to of atrogin-1 and result in the of to the ubiquitin ligase hypertrophy be in hearts that to that diminish In that the factors of cardiac hypertrophy. to be in the reverse of the heart that occurs during with ventricular Circ. Res. PubMed Scopus Google Scholar), treatment of K. E. K. J. K. P. 2004; PubMed Scopus Google Scholar), and (7Shiojima I. Yefremashvili M. Luo Z. Kureishi Y. Takahashi A. Tao J. Rosenzweig A. Kahn C.R. Abel E.D. Walsh K. J. Biol. Chem. 2002; 277: 37670-37677Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). cardiac hypertrophy is associated with an increased risk of cardiac and heart studies the transcriptional result in the of the treatment of heart
Skurk et al. (Tue,) conducted a other in Cardiac hypertrophy. FOXO3a gene transfer was evaluated on Cardiac myocyte size and atrogin-1 expression. FOXO3a gene transfer prevented IGF- and stretch-induced hypertrophy in vitro and significantly reduced cardiomyocyte size in vivo by activating an atrogene transcriptional program.