title: Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling.
abstract: OBJECTIVE
  Tissue transglutaminase (tTG) is induced in injured and remodelling tissues, and modulates cellular phenotype, while contributing to matrix cross-linking. Our study tested the hypothesis that tTG may be expressed in the pressure-overloaded myocardium, and may regulate cardiac function, myocardial fibrosis and chamber remodelling.
  
  
  RESULTS
  In order to test the hypothesis, wild-type and tTG null mice were subjected to pressure overload induced through transverse aortic constriction. Moreover, we used isolated cardiac fibroblasts and macrophages to dissect the mechanisms of tTG-mediated actions. tTG expression was upregulated in the pressure-overloaded mouse heart and was localized in cardiomyocytes, interstitial cells, and in the extracellular matrix. In contrast, expression of transglutaminases 1, 3, 4, 5, 6, 7 and FXIII was not induced in the remodelling myocardium. In vitro, transforming growth factor (TGF)-β1 stimulated tTG synthesis in cardiac fibroblasts and in macrophages through distinct signalling pathways. tTG null mice had increased mortality and enhanced ventricular dilation following pressure overload, but were protected from diastolic dysfunction. tTG loss was associated with a hypercellular cardiac interstitium, reduced collagen cross-linking, and with accentuated matrix metalloproteinase (MMP)2 activity in the pressure-overloaded myocardium. In vitro, tTG did not modulate TGF-β-mediated responses in cardiac fibroblasts; however, tTG loss was associated with accentuated proliferative activity. Moreover, when bound to the matrix, recombinant tTG induced synthesis of tissue inhibitor of metalloproteinases (TIMP)-1 through transamidase-independent actions.
  
  
  CONCLUSIONS
  Following pressure overload, endogenous tTG mediates matrix cross-linking, while protecting the remodelling myocardium from dilation by exerting matrix-preserving actions.
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY 10021, USA.
authors.forename: Arti V
authors.initials: AV
authors.lastname: Shinde
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY 10021, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Dobaczewski
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY 10021, USA.
authors.forename: Judith J
authors.initials: JJ
authors.lastname: de Haan
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY 10021, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY 10021, USA.
authors.forename: Kang-Kon
authors.initials: KK
authors.lastname: Lee
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY 10021, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY 10021, USA.
authors.forename: Ya
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY 10021, USA.
authors.forename: Waqas
authors.initials: W
authors.lastname: Hanif
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY 10021, USA.
authors.forename: Inderpreet
authors.initials: I
authors.lastname: Kaur Madahar
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY 10021, USA.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Paulino
authors.affiliation: Biochemistry IDI-IRCCS Laboratory, Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.affiliation: Department of Medicine (Cardiology), Albert Einstein College of Medicine, The Wilf Family Cardiovascular Research Institute, Bronx, NY 10021, USA.|Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology; D008297:Male; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D011312:Pressure; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D016212:Transforming Growth Factor beta / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D016212:Transforming Growth Factor beta; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Cardiac fibrosis; Collagen cross-linking; Fibroblast; Matrix metalloproteinase; Transglutaminase