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.