title: Genetic Analysis of Connective Tissue Growth Factor as an Effector of Transforming Growth Factor β Signaling and Cardiac Remodeling.
abstract: The matricellular secreted protein connective tissue growth factor (CTGF) is upregulated in response to cardiac injury or with transforming growth factor β (TGF-β) stimulation, where it has been suggested to function as a fibrotic effector. Here we generated transgenic mice with inducible heart-specific CTGF overexpression, mice with heart-specific expression of an activated TGF-β mutant protein, mice with heart-specific deletion of Ctgf, and mice in which Ctgf was also deleted from fibroblasts in the heart. Remarkably, neither gain nor loss of CTGF in the heart affected cardiac pathology and propensity toward early lethality due to TGF-β overactivation in the heart. Also, neither heart-specific Ctgf deletion nor CTGF overexpression altered cardiac remodeling and function with aging or after multiple acute stress stimuli. Cardiac fibrosis was also unchanged by modulation of CTGF levels in the heart with aging, pressure overload, agonist infusion, or TGF-β overexpression. However, CTGF mildly altered the overall cardiac response to TGF-β when pressure overload stimulation was applied. CTGF has been proposed to function as a critical TGF-β effector in underlying tissue remodeling and fibrosis throughout the body, although our results suggest that CTGF is of minimal importance and is an unlikely therapeutic vantage point for the heart.
authors: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: Federica
authors: F
authors: Accornero
authors: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: Jop H
authors: JH
authors: van Berlo
authors: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: Robert N
authors: RN
authors: Correll
authors: Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: John W
authors: JW
authors: Elrod
authors: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: Michelle A
authors: MA
authors: Sargent
authors: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors: Allen
authors: A
authors: York
authors: Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Joseph E
authors: JE
authors: Rabinowitz
authors: Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors: Andrew
authors: A
authors: Leask
authors: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA Howard Hughes Medical Institute, Cincinnati, Ohio, USA jeff.molkentin@cchmc.org.
authors: Jeffery D
authors: JD
authors: Molkentin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics* / Q000378:metabolism*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D015870:Gene Expression; D018390:Gene Targeting; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor