Journal
CARDIOVASCULAR RESEARCH
Volume 113, Issue 8, Pages 892-905Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvx053
Keywords
Transglutaminase; Cardiac fibrosis; Collagen cross-linking; Fibroblast; Matrix metalloproteinase
Categories
Funding
- National Institutes of Health [R01 HL76246, R01 HL85440]
- Department of Defense [PR151134, PR151029]
- American Heart Association Founders' affiliate
- Medical Research Council [MC_U132670600] Funding Source: researchfish
- MRC [MC_U132670600] Funding Source: UKRI
Ask authors/readers for more resources
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)-beta 1 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-beta-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available