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Prevention of SU5416-Induced Pulmonary Hypertension in a TGF beta Dependent Genetic Mouse Model of Scleroderma Using the Endothelin Receptor Antagonist Macitentan.

Derret-Smith, E, Sobanski, V, Trinder, S, Gilbane, A, Iglarz, M, Abraham, D, Holmes, A and Denton, C (2014) Prevention of SU5416-Induced Pulmonary Hypertension in a TGF beta Dependent Genetic Mouse Model of Scleroderma Using the Endothelin Receptor Antagonist Macitentan. In: 2014 ACR/ARHP Annual Meeting, 2014-11-14 - 2014-11-19, Boston, MA.

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Abstract

Background/Purpose: Pulmonary arterial hypertension (PAH) is an important complication of systemic sclerosis (SSc) that occurs in around 10% of cases. We have previously shown that a TGFbeta dependent transgenic mouse strain (TβRIIΔk-fib) is susceptible to organ based pathology relevant to SSc and that pulmonary endothelial injury is associated with development of PH with perturbed VEGF, BMP and endothelin signalling. In this study, we have prevented the development of PH in this mouse strain using macitentan, a potent endothelin receptor antagonist recently licensed to treat PAH in connective tissue disease based upon a significant effect on morbidity and mortality in PAH. Methods: SU5416, a VEGF receptor inhibitor, was administered to all TβRIIΔk-fib transgenic (TG) mice and littermate wildtype (WT) animals to induce endothelial injury with subsequent endoluminal proliferation and PH in transgenic mice only. Mice were treated with either 50mg/kg macitentan daily by oral gavage or vehicle alone (n=8 each group). The development of PH in each group was assessed by histology and immunohistochemistry of vessel architecture, in vivo haemodynamic studies and RV mass index measurements. Results: Compared with WT littermates, after SU5416, all TG mice developed a prominent perivascular chronic inflammatory infiltrate and smooth muscle layer hypertrophy, as previously described. RV mass index was elevated in TG animals receiving vehicle compared to other groups (TG vehicle 0.29±0.007, TG macitentan 0.24±0.007, p<0.05). The increase in RV systolic pressure in TG animals treated with SU5416 was also abrogated by macitentan (figure 1) without any significant change in systemic arterial blood pressure in any group. Explanted TG lung fibroblasts showed an increase in proliferation and migration with upregulation of VEGF and TGFbeta signalling and downregulation of endothelin receptor A compared with WT littermates. There was obliterative pulmonary arteriolar occlusion in 21% of vessels in TG mice treated with vehicle. In contrast, no vessels in WT mice or TG mice treated with macitentan developed this histological change. Conclusion: Macitentan prevents the development of histological and haemodynamic PH in this mouse model of SSc. These findings support a pivotal role for perturbed endothelin activity in a model that is induced by altered TGFbeta signalling and triggered by experimental VEGF inhibition. It underpins the value of this model as a platform for experimental therapeutic studies as well as providing insight into pathogenic mechanisms of disease.

Item Type: Conference or Workshop Item (Conference Abstract)
Subjects : Biosciences
Authors :
NameEmailORCID
Derret-Smith, EUNSPECIFIEDUNSPECIFIED
Sobanski, VUNSPECIFIEDUNSPECIFIED
Trinder, Ss.trinder@surrey.ac.ukUNSPECIFIED
Gilbane, AUNSPECIFIEDUNSPECIFIED
Iglarz, MUNSPECIFIEDUNSPECIFIED
Abraham, DUNSPECIFIEDUNSPECIFIED
Holmes, AUNSPECIFIEDUNSPECIFIED
Denton, CUNSPECIFIEDUNSPECIFIED
Date : 1 October 2014
Contributors :
ContributionNameEmailORCID
publisherWiley-Blackwell, UNSPECIFIEDUNSPECIFIED
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:45
Last Modified : 18 May 2017 12:43
URI: http://epubs.surrey.ac.uk/id/eprint/829055

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