Gilbane, A; (2015) Aberrant TGFβ/BMP signalling in connective tissue disease associated pulmonary hypertension. Doctoral thesis , UCL (University College London).

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Abstract

Up to 10 percent of systemic sclerosis (SSc) patients develop pulmonary arterial hypertension (PAH). This risk persists throughout the disease and is time dependent, suggesting that SSc operates as a susceptibility factor. Outcomes for SSc-PAH patients remain poor compared with heritable (HPAH) or idiopathic (HPAH) forms, despite clinical and pathological similarities. Whereas susceptibility in HPAH and HPAH is strongly associated with gene mutations that lead to reduced expression of functional bone morphogenetic protein type II receptor (BMPRII), these mutations have not been observed in SSc-PAH. My initial aim was to investigate BMPRII expression and downstream signalling pathways in whole lung tissue and explant cultured fibroblasts derived from a murine model of SSc (TβRIIΔk-fib) that is susceptible to developing PAH Complementary studies examined SSc or control lung tissue and fibroblasts. My results suggest reduced BMPRII levels, impaired signalling and altered receptor turnover could be due to increased TGFβ activity in a model of SSc-PAH. Similarly a significant reduction in BMPRII expression is observed in SSc lung tissue and fibroblasts. Increased proteasomal degradation of BMPRII appears to underlie this and may result from heightened TGFβ activity. Proteasomal inhibition restored BMPRII expression and cellular responses. Collectively suggesting that impaired TGFβ/BMP signalling leading to increased receptor degradation, may promote PAH susceptibility in SSc and provide a unifying mechanism across different forms of PAH. Since more than one cell type contribute to the development of PAH and the pathophysiology of the disease BMPRII expression and TGFβ responses in pulmonary arterial smooth muscle cells (PASMCs) were also investigated. Initial studies generated a synthetic “disease” like PASMC that also displayed a reduction in BMPRII expression and increased response to TGFβ, which was similar to IPAH cells Finally, the role of epigenetic inhibition in the TβRIIΔk-fib model was investigated. The epigenetic inhibitor JQ1 was able to attenuate the spontaneous development of PAH in the TβRIIΔk-fib model of PAH. Taken together, work described in this thesis strongly suggests that a reduction in BMPRII is a susceptibility factor to the development of PAH in a pre-clinical model of SSc and in SSc patients.

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