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Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling
- Source :
- Cardiovascular Research. 113:892-905
- Publication Year :
- 2017
- Publisher :
- Oxford University Press (OUP), 2017.
-
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 pressure-overloaded 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)-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.
- Subjects :
- Male
0301 basic medicine
Physiology
Cardiac fibrosis
Tissue transglutaminase
030204 cardiovascular system & hematology
Matrix metalloproteinase
Extracellular matrix
03 medical and health sciences
0302 clinical medicine
GTP-Binding Proteins
Transforming Growth Factor beta
Physiology (medical)
Pressure
medicine
Animals
Myocytes, Cardiac
Protein Glutamine gamma Glutamyltransferase 2
Fibroblast
Mice, Knockout
Pressure overload
Transglutaminases
Ventricular Remodeling
biology
Settore BIO/11
Chemistry
Myocardium
Fibroblasts
medicine.disease
Fibrosis
Extracellular Matrix
Cell biology
030104 developmental biology
medicine.anatomical_structure
biology.protein
Female
Hypertrophy, Left Ventricular
Myocardial fibrosis
Cardiology and Cardiovascular Medicine
Transforming growth factor
Subjects
Details
- ISSN :
- 17553245 and 00086363
- Volume :
- 113
- Database :
- OpenAIRE
- Journal :
- Cardiovascular Research
- Accession number :
- edsair.doi.dedup.....e4de6f7be9885e5888462ec2a74de7ef