Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling
| Autor: | Wei Chen, Marcin Dobaczewski, Judith J. de Haan, Nikolaos G. Frangogiannis, Ying Xia, Inderpreet Kaur Madahar, Ya Su, Waqas Hanif, Kang Kon Lee, Gerry Melino, Victor Paulino, Arti V. Shinde, Amit Saxena |
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| Rok vydání: | 2017 |
| Předmět: |
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 |
| Zdroj: | Cardiovascular Research. 113:892-905 |
| ISSN: | 1755-3245 0008-6363 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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