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

Zhuo Wang, Daniel J. Stuckey, Colin E. Murdoch, Patrizia Camelliti, Gregory Y.H. Lip, Martin Griffin

Research output: Contribution to journalArticle

Abstract

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.
LanguageEnglish
Article number613
JournalCell Death and Disease
Volume9
Early online date27 Apr 2018
DOIs
Publication statusE-pub ahead of print - 27 Apr 2018

Fingerprint

Fibrosis
Myofibroblasts
transglutaminase 2
Angiotensin II
Ligation
Heart Diseases
Coronary Vessels
Heart Failure
Myocardial Infarction
Staining and Labeling
Pressure
Enzymes
Therapeutics
Proteins

Bibliographical note

© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction
in any mediumor format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if
changesweremade. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If
material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Funding: D.J.S. is a BHF Intermediate Basic Science
Research Fellow (FS/15/33/31608). W.Z. was partially funded through the EC
Marie Curie ITN TRANSPATH (Grant No. 289964). C.E.M. is a Marie Skłodowska
Curie International Incoming Fellow (Grant No. 626633).

Cite this

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title = "Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor",
abstract = "Cardiac fibrosis is implicit in all forms of heart disease but there are no effective treatments. In this report, weinvestigate the role of the multi-functional enzyme Transglutaminase 2 (TG2) in cardiac fibrosis and assess its potentialas a therapeutic target. Here we describe the use a highly selective TG2 small-molecule inhibitor to test the efficacy ofTG2 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 inducedfocal cardiac fibrosis through myocardial infarction by ligation of the left anterior descending coronary artery (AMImodel). In the AMI model, in vivo MRI showed that the TG2 inhibitor 1–155 significantly reduced infarct size by over50{\%} and reduced post-infarct remodelling at 20 days post insult. In both models, Sirius red staining for collagendeposition and levels of the TG2-mediated protein crosslink ε(γ-glutamyl)lysine were significantly reduced. No cardiacrupture or obvious signs of toxicity were observed. To provide a molecular mechanism for TG2 involvement in cardiacfibrosis, 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 anew role for TG2 in regulating TGFβ1 signalling in addition to its role in latent TGFβ1 activation. In conclusion, TG2 hasa role in cardiac fibrosis through activation of myofibroblasts and matrix deposition. TG2 inhibition using a selectivesmall-molecule inhibitor can attenuate cardiac fibrosis.",
author = "Zhuo Wang and Stuckey, {Daniel J.} and Murdoch, {Colin E.} and Patrizia Camelliti and Lip, {Gregory Y.H.} and Martin Griffin",
note = "{\circledC} The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any mediumor format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changesweremade. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Funding: D.J.S. is a BHF Intermediate Basic Science Research Fellow (FS/15/33/31608). W.Z. was partially funded through the EC Marie Curie ITN TRANSPATH (Grant No. 289964). C.E.M. is a Marie Skłodowska Curie International Incoming Fellow (Grant No. 626633).",
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Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor. / Wang, Zhuo; Stuckey, Daniel J.; Murdoch, Colin E.; Camelliti, Patrizia; Lip, Gregory Y.H.; Griffin, Martin.

In: Cell Death and Disease, Vol. 9, 613, 27.04.2018.

Research output: Contribution to journalArticle

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AU - Wang, Zhuo

AU - Stuckey, Daniel J.

AU - Murdoch, Colin E.

AU - Camelliti, Patrizia

AU - Lip, Gregory Y.H.

AU - Griffin, Martin

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AB - Cardiac fibrosis is implicit in all forms of heart disease but there are no effective treatments. In this report, weinvestigate the role of the multi-functional enzyme Transglutaminase 2 (TG2) in cardiac fibrosis and assess its potentialas a therapeutic target. Here we describe the use a highly selective TG2 small-molecule inhibitor to test the efficacy ofTG2 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 inducedfocal cardiac fibrosis through myocardial infarction by ligation of the left anterior descending coronary artery (AMImodel). In the AMI model, in vivo MRI showed that the TG2 inhibitor 1–155 significantly reduced infarct size by over50% and reduced post-infarct remodelling at 20 days post insult. In both models, Sirius red staining for collagendeposition and levels of the TG2-mediated protein crosslink ε(γ-glutamyl)lysine were significantly reduced. No cardiacrupture or obvious signs of toxicity were observed. To provide a molecular mechanism for TG2 involvement in cardiacfibrosis, 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 anew role for TG2 in regulating TGFβ1 signalling in addition to its role in latent TGFβ1 activation. In conclusion, TG2 hasa role in cardiac fibrosis through activation of myofibroblasts and matrix deposition. TG2 inhibition using a selectivesmall-molecule inhibitor can attenuate cardiac fibrosis.

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