Therapeutic Targeting of BMP and TGF-β Signalling Pathways for the Resolution of Pulmonary Arterial Hypertension

Vascular remodelling due to excessive proliferation and apoptosis resistance of pulmonary arterial smooth muscle (PASMCs) and endothelial cells (ECs) has been attributed to the pathogenesis of pulmonary arterial hypertension (PAH). It is an incurable cardiovascular disorder, which leads to right heart failure and death, if left untreated. Heterozygous germline mutations in the bone morphogenetic protein receptor type II (BMPR2) have been linked with the majority (~75%) of the familial form of the disease (HPAH). Mutations in the BMPR2 gene impinge upon the BMP signalling which perturbs the balance between BMP and TGF-β pathways leading to the clinical course of the disease. Current therapies were discovered prior to the knowledge that PAH has substantial genetic components. Hence, this study aims to identify novel therapeutic intervention and provide novel insights into how the dysfunctional BMPRII signalling contributes to the pathogenesis of PAH. This work demonstrates that cryptolepines and FDA approved drugs (doxorubicin, taxol, digitoxin and podophyllotoxin) inhibit the excessive proliferation and induce apoptosis in BMPR2 mutant PASMCs by modulating the BMP and TGF-β pathways. Moreover, established drug PTC124 has also been tested but has failed to promote translational readthrough. I have also shown that dysregulated apoptosis of PASMCs and HPAECs is mediated through the BMPRII-ALK1-BclxL axis. Finally, the siRNA screen targeting approximately 1000 genes has identified novel proteins including PPP1CA, IGF-1R, MPP1, MCM5 and SRC each capable of modulating the BMPRII signalling. Taken together, this study for the very first time has identified novel compounds with pro-BMP and anti-TGFβ activities which may provide therapeutic intervention prior to or after the onset of PAH.

Grantor dc:publisher.institution

University of Bradford

Year dc:date.issued

2018

Author dc:creator

• Sharmin, Nahid

Advisors dc:contributor.advisor

• Nasim, Md. Talat
• Graham, Anne M

• Pulmonary arterial hypertension (PAH)
• Bone morphogenetic protein (BMP)
• Bone morphogenetic protein receptor type II (BMPR2)
• Transforming growth factor β (TGF-β)
• Pulmonary arterial smooth muscle cell
• Endothelial cell
• Cryptolepine
• Inhibitor of differentiation
• Plasminogen activator inhibitor
• Apoptosis
• Proliferation
• Therapeutic intervention

Statement dc:rights

• <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>.

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10454/17177

OAI identifier oai:identifier

oai:bradscholars.brad.ac.uk:10454/17177