TY - JOUR
T1 - Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling
AU - Shinde, Arti V.
AU - Dobaczewski, Marcin
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.
N1 - Publisher Copyright:
© The Author 2017.
PY - 2017/7/1
Y1 - 2017/7/1
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.
KW - Cardiac fibrosis
KW - Collagen cross-linking
KW - Fibroblast
KW - Matrix metalloproteinase
KW - Transglutaminase
UR - http://www.scopus.com/inward/record.url?scp=85021837311&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85021837311&partnerID=8YFLogxK
U2 - 10.1093/cvr/cvx053
DO - 10.1093/cvr/cvx053
M3 - Article
C2 - 28371893
AN - SCOPUS:85021837311
SN - 0008-6363
VL - 113
SP - 892
EP - 905
JO - Cardiovascular research
JF - Cardiovascular research
IS - 8
ER -