title: The transcription factor Eya2 prevents pressure overload-induced adverse cardiac remodeling.
abstract: Eyes absent 2 (Eya2) is a transcription factor involved in a number of cellular and developmental processes. We have previously shown that Eya2 is up-regulated during regression of cardiac hypertrophy and blocks phenylephrine-induced development of cardiomyocyte hypertrophy in vitro, suggesting that Eya2 is a negative regulator of cardiac hypertrophy. In this study, we generated transgenic mice with cardiac-specific overexpression of Eya2 to elucidate the in vivo function of Eya2 in cardiac remodeling. Mild cardiac hypertrophy developed in Eya2 transgenic mice under baseline conditions with no obvious structural or functional defects. Eya2 overexpression inhibited development of cardiac hypertrophy as judged by the abrogation of increases in heart weight and cross-sectional cell surface areas and re-activation of fetal genes under pressure overload (4 weeks). Eya2 overexpression also prevented wall thinning, ventricular dilation, and deterioration of cardiac function as well as fibrosis and inflammation in the heart under long-term pressure overload (12 weeks). Gene expression profiling using the parametric analysis of gene set enrichment (PAGE) method revealed that gene sets related to mitochondrial biogenesis and metabolism were elevated in the Eya2 transgenic mice. We also observed that the PI3K/Akt/mTOR signaling cascade was preserved in the Eya2 transgenic mice, while it was significantly reduced in the wild type littermates under pressure overload. These results demonstrate that Eya2 prevents adverse cardiac remodeling under pressure overload partly through altering metabolic gene expression and preserving PI3K/Akt/mTOR signaling pathway.
authors.affiliation: Department of Life Science, Global Research Lab, Gwangju Institute of Science and Technology, Buk-gu, Gwangju, South Korea.
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Dong Kwon
authors.initials: DK
authors.lastname: Yang
authors.forename: Bo Youn
authors.initials: BY
authors.lastname: Choi
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Lee
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Dongtak
authors.initials: D
authors.lastname: Jeong
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D005355:Fibrosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism*; D009928:Organ Specificity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011312:Pressure; D011494:Protein Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014463:Ultrasonography; D020257:Ventricular Remodeling
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017027:Protein Tyrosine Phosphatases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C546843:mTOR protein, mouse; C501159:Eya2 protein, mouse