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

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

Access and allocation in climate change adaptation

As climate change impacts become increasingly apparent, adaptation becomes increasingly urgent. Accordingly, adaptation to climate change has shifted towards the centre of attention in both policy and research. In this article, we review the last 10 years of adaptation research (2008–2018), with a focus on work within the Earth System Governance network. We use the lens of access and allocation to structure our review and examine how adaptation affects, and is affected by, access to basic needs, basic rights, and decision-making on the one hand, as well as allocation of responsibilities, resources, and risks on the other. We find that questions of justice, equity, and fairness are fundamental to all dimensions of adaptation. The access perspective, for example, suggests that we need to assess vulnerability, understood broadly, while the allocation perspective focuses on questions of responsibility for being vulnerable, e.g. when people live, or move to, hazard-prone areas exposed to climate risk. This also relates to questions of who is responsible for selecting, implementing, and funding adaptation measures. Overall, we find that the framework of “access and allocation” and its subcategories offer a detailed approach to adaptation and adaptation research, but that it is not intuitive. The notion of “climate justice” seems to resonate more with both academic and policy debates