Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling

Arti V. Shinde, Marcin Dobaczewski, Judith J. De Haan, Amit Saxena, Kang Kon Lee, Ying Xia, Wei Chen, Ya Su, Waqas Hanif, Inderpreet Kaur Madahar, Victor M. Paulino, Gerry Melino, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Aims 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 pressureoverloaded myocardium, and may regulate cardiac function, myocardial fibrosis and chamber remodelling.Methods and 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)-b1 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 pressureoverloaded myocardium.In vitro, tTG did not modulate TGF-b-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.All rights reserved.

Original languageEnglish (US)
Pages (from-to)892-905
Number of pages14
JournalCardiovascular research
Issue number8
StatePublished - Jul 1 2017


  • Cardiac fibrosis
  • Collagen cross-linking
  • Fibroblast
  • Matrix metalloproteinase
  • Transglutaminase

ASJC Scopus subject areas

  • General Medicine


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