title: TGFbeta inducible early gene-1 (TIEG1) and cardiac hypertrophy: Discovery and characterization of a novel signaling pathway.
abstract: Cellular mechanisms causing cardiac hypertrophy are currently under intense investigation. We report a novel finding in the TGFbeta inducible early gene (TIEG) null mouse implicating TIEG1 in cardiac hypertrophy. The TIEG(-/-) knock-out mouse was studied. Male mice age 4-16 months were characterized (N = 86 total) using echocardiography, transcript profiling by gene microarray, and immunohistochemistry localized upregulated genes for determination of cellular mechanism. The female mice (N = 40) did not develop hypertrophy or fibrosis. The TIEG(-/-) knock-out mouse developed features of cardiac hypertrophy including asymmetric septal hypertrophy, an increase in ventricular size at age 16 months, an increase (214%) in mouse heart/weight body weight ratio TIEG(-/-), and an increase in wall thickness in TIEG(-/-) mice of (1.85 +/- 0.21 mm), compared to the control (1.13 +/- 0.15 mm, P < 0.04). Masson Trichrome staining demonstrated evidence of myocyte disarray and myofibroblast fibrosis. Microarray analysis of the left ventricles demonstrated that TIEG(-/-) heart tissues expressed a 13.81-fold increase in pituitary tumor-transforming gene-1 (Pttg1). An increase in Pttg1 and histone H3 protein levels were confirmed in the TIEG(-/-) mice hearts tissues. We present evidence implicating TIEG and possibly its target gene, Pttg1, in the development of cardiac hypertrophy in the TIEG null mouse.
authors.affiliation: Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. n-rajamannan@northwestern.edu
authors.forename: Nalini M
authors.initials: NM
authors.lastname: Rajamannan
authors.forename: Malayannan
authors.initials: M
authors.lastname: Subramaniam
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Abraham
authors.forename: Vlad C
authors.initials: VC
authors.lastname: Vasile
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: David G
authors.initials: DG
authors.lastname: Monroe
authors.forename: Teng-Leong
authors.initials: TL
authors.lastname: Chew
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Spelsberg
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D005260:Female; D006657:Histones / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009363:Neoplasm Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D064249:Securin; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D064249:Securin; D014157:Transcription Factors; C569958:KLF10 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors