Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling

Shinde, Arti V.; Dobaczewski, Marcin; Haan, Judith J. de; Saxena, Amit; Lee, Kang Kon; Xia, Ying; Chen, Wei; Su, Ya; Hanif, Waqas; Madahar, Inderpreet Kaur; Paulino, Victor; Melino, Gerry; Frangogiannis, Nikolaos G.

doi:10.1093/cvr/cvx053

Cited by 37 publications

(35 citation statements)

References 41 publications

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“…Importantly, this observation of a reduction in deposited collagen which when crosslinked by TG2 prevents turnover of the fibrotic collagen matrix mirrors that found in a recent publication using the transverse aorta constriction model (TAC) in TG2 ko mice 22 . In this TG2 ko model in the wt control mice increased TG2 expression was found in cardiomyocytes, interstitial cells and in the extracellular matrix, but increases in TG2 activity as defined by an increase in ε(γ-glutamyl) lysine crosslink was not measured.…”

Section: Discussionsupporting

confidence: 82%

Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor

et al. 2018

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Cardiac fibrosis is implicit in all forms of heart disease but there are no effective treatments. In this report, we investigate the role of the multi-functional enzyme Transglutaminase 2 (TG2) in cardiac fibrosis and assess its potential as a therapeutic target. Here we describe the use a highly selective TG2 small-molecule inhibitor to test the efficacy of TG2 inhibition as an anti-fibrotic therapy for heart failure employing two different in vivo models of cardiac fibrosis: Progressively induced interstitial cardiac fibrosis by pressure overload using angiotensin II infusion: Acutely induced focal cardiac fibrosis through myocardial infarction by ligation of the left anterior descending coronary artery (AMI model). In the AMI model, in vivo MRI showed that the TG2 inhibitor 1–155 significantly reduced infarct size by over 50% and reduced post-infarct remodelling at 20 days post insult. In both models, Sirius red staining for collagen deposition and levels of the TG2-mediated protein crosslink ε(γ-glutamyl)lysine were significantly reduced. No cardiac rupture or obvious signs of toxicity were observed. To provide a molecular mechanism for TG2 involvement in cardiac fibrosis, we show that both TGFβ1-induced transition of cardiofibroblasts into myofibroblast-like cells and TGFβ1-induced EndMT, together with matrix deposition, can be attenuated by the TG2 selective inhibitor 1–155, suggesting a new role for TG2 in regulating TGFβ1 signalling in addition to its role in latent TGFβ1 activation. In conclusion, TG2 has a role in cardiac fibrosis through activation of myofibroblasts and matrix deposition. TG2 inhibition using a selective small-molecule inhibitor can attenuate cardiac fibrosis.

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Section: Discussionsupporting

confidence: 82%

Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor

et al. 2018

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“…Light microscopy and polarized light microscopy was used to label collagen fibers in the atrium, as previously described (33),(19). Briefly, paraffin sections (5 μ thick) were stained using picrosirius red.…”

Section: 2 Materials and Methodsmentioning

confidence: 99%

“…Mouse models of myocardial disease have been extensively used to study the pathophysiology of myocardial infarction and heart failure (14),(15),(16),(17),(18),(19),(20). Although sophisticated imaging modalities, histopathologic studies and molecular approaches are used to study remodeling of the left ventricle, atrial pathology is often ignored.…”

Section: 1 Introductionmentioning

confidence: 99%

Left atrial remodeling, hypertrophy, and fibrosis in mouse models of heart failure

Hanif¹,

Alex²,

Su³

et al. 2017

Cardiovascular Pathology

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Left ventricular dysfunction increases left atrial pressures and causes atrial remodeling. In human subjects, increased left atrial size is a powerful predictor of mortality and adverse events in a broad range of cardiac pathologic conditions. Moreover, structural remodeling of the atrium plays an important role in the pathogenesis of atrial tachyarrhythmias. Despite the potential value of the atrium in assessment of functional endpoints in myocardial disease, atrial pathologic alterations in mouse models of left ventricular disease have not been systematically investigated. Our study describes the geometric, morphologic and structural changes in experimental mouse models of cardiac pressure overload (induced through transverse aortic constriction), myocardial infarction and diabetes. Morphometric and histological analysis showed that pressure overload was associated with left atrial dilation, increased left atrial mass, loss of myofibrillar content in a subset of atrial cardiomyocytes, atrial cardiomyocyte hypertrophy, and atrial fibrosis. In mice undergoing non-reperfused myocardial infarction protocols, marked left ventricular systolic dysfunction was associated with left atrial enlargement, atrial cardiomyocyte hypertrophy and atrial fibrosis. Both infarcted animals and pressure overloaded mice exhibited attenuation and perturbed localization of atrial connexin-43 immunoreactivity, suggesting gap junctional remodeling. In the absence of injury, obese diabetic db/db mice had diastolic dysfunction, associated with atrial dilation, atrial cardiomyocyte hypertrophy and mild atrial fibrosis. Considering the challenges in assessment of clinically relevant functional endpoints in mouse models of heart disease, study of atrial geometry and morphology may serve as an important new tool for evaluation of ventricular function.

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“…tTG is constitutively expressed in normal mammalian myocardium, and is upregulated in injured and failing hearts [ 6 ]. In a recently published study [ 1 ], we provided the first evidence suggesting an important role for tissue transglutaminase in the pathogenesis of heart failure. We used a mouse model of transverse aortic constriction that recapitulates the cardiomyopathy of pressure overload, one of the most common pathophysiologic conditions associated with heart failure in human patients.…”

Section: Ttg In Heart Diseasementioning

confidence: 99%

“…First described in the 1950s, tissue tranglutaminase (tTG, transglutaminase 2), is a unique multifunctional member of the transglutaminase family with effects that extend beyond its enzymatic actions. A recently published study demonstrates an important role for endogenous tTG in the pathogenesis of pressure overload-induced heart failure, suggesting crosslinking actions that promote diastolic dysfunction, and protective matrix-preserving effects that prevent chamber dilation [ 1 ]. The functions of tTG in the failing heart may involve both enzymatic and non-enzymatic effects with several different cellular targets and a wide range of molecular interactions.…”

mentioning

confidence: 99%

Tissue transglutaminase in the pathogenesis of heart failure

Shinde

Frangogiannis

2017

Cell Death Differ

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Tissue transglutaminase induction in the pressure-overloaded myocardium regulates matrix remodelling

Abstract: Following pressure overload, endogenous tTG mediates matrix cross-linking, while protecting the remodelling myocardium from dilation by exerting matrix-preserving actions.

Cited by 37 publications

References 41 publications

Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor

Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor

Left atrial remodeling, hypertrophy, and fibrosis in mouse models of heart failure

Tissue transglutaminase in the pathogenesis of heart failure

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