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

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Abstract

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
Volume113
Issue number8
DOIs
StatePublished - Jul 1 2017

Fingerprint

Myocardium
Pressure
Fibroblasts
Transforming Growth Factors
transglutaminase 2
Dilatation
Macrophages
Tissue Inhibitor of Metalloproteinase-1
Matrix Metalloproteinase 2
Cardiac Myocytes
Constriction
Extracellular Matrix
Fibrosis
Collagen
Phenotype
Mortality

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling. / Shinde, Arti V.; Dobaczewski, Marcin; De Haan, Judith J.; Saxena, Amit; Lee, Kang Kon; Xia, Ying; Chen, Wei; Su, Ya; Hanif, Waqas; Kaur Madahar, Inderpreet; Paulino, Victor M.; Melino, Gerry; Frangogiannis, Nikolaos G.

In: Cardiovascular Research, Vol. 113, No. 8, 01.07.2017, p. 892-905.

Research output: Contribution to journalArticle

Shinde, AV, Dobaczewski, M, De Haan, JJ, Saxena, A, Lee, KK, Xia, Y, Chen, W, Su, Y, Hanif, W, Kaur Madahar, I, Paulino, VM, Melino, G & Frangogiannis, NG 2017, 'Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling', Cardiovascular Research, vol. 113, no. 8, pp. 892-905. https://doi.org/10.1093/cvr/cvx053
Shinde, Arti V. ; Dobaczewski, Marcin ; De Haan, Judith J. ; Saxena, Amit ; Lee, Kang Kon ; Xia, Ying ; Chen, Wei ; Su, Ya ; Hanif, Waqas ; Kaur Madahar, Inderpreet ; Paulino, Victor M. ; Melino, Gerry ; Frangogiannis, Nikolaos G. / Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling. In: Cardiovascular Research. 2017 ; Vol. 113, No. 8. pp. 892-905.
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AU - De Haan, Judith J.

AU - Saxena, Amit

AU - Lee, Kang Kon

AU - Xia, Ying

AU - Chen, Wei

AU - Su, Ya

AU - Hanif, Waqas

AU - Kaur Madahar, Inderpreet

AU - Paulino, Victor M.

AU - Melino, Gerry

AU - Frangogiannis, Nikolaos G.

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N2 - 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.

AB - 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.

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