BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH)
Yes === Pulmonary Arterial Hypertension (PAH) is a devastating cardiovascular disorder characterised by the remodelling of pre-capillary pulmonary arteries. The vascular remodelling observed in PAH patients results from excessive proliferation and apoptosis resistance of pulmonary arterial smooth mu...
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ndltd-BRADFORD-oai-bradscholars.brad.ac.uk-10454-168852019-08-31T03:05:01Z BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH) Chowdhury, H.M. Sharmin, N. Yuzbasioglu Baran, M. Long, L. Morrell, N.W. Trembath, R.C. Nasim, Md. Talat Pulmonary Arterial Hypertension (PAH) Bone morphogenetic protein (BMPRII) BMPRII deficiency Apoptosis Yes Pulmonary Arterial Hypertension (PAH) is a devastating cardiovascular disorder characterised by the remodelling of pre-capillary pulmonary arteries. The vascular remodelling observed in PAH patients results from excessive proliferation and apoptosis resistance of pulmonary arterial smooth muscle (PASMCs) and endothelial cells (PAECs). We have previously demonstrated that mutations in the type II receptor for bone morphogenetic protein (BMPRII) underlie the majority of the familial and inherited forms of the disease. We have further demonstrated that BMPRII deficiency promotes excessive proliferation and attenuates apoptosis in PASMCs, but the underlying mechanisms remain unclear. The major objective of this study is to investigate how BMPRII deficiency impairs apoptosis in PAH. Using multidisciplinary approaches, we demonstrate that deficiency in the expression of BMPRII impairs apoptosis by modulating the alternative splicing of the apoptotic regulator, Bcl-x (B-cell lymphoma X) transcripts: a finding observed in circulating leukocytes and lungs of PAH subjects, hypoxia-induced PAH rat lungs as well as in PASMCs and PAECs. BMPRII deficiency elicits cell specific effects: promoting the expression of Bcl-xL transcripts in PASMCs whilst inhibiting it in ECs, thus exerting differential apoptotic effects in these cells. The pro-survival effect of BMPRII receptor is mediated through the activin receptor like kinase 1 (ALK1) but not the ALK3 receptor. Finally, we show that BMPRII interacts with the ALK1 receptor and pathogenic mutations in the BMPR2 gene abolish this interaction. Taken together, dysfunctional BMPRII responsiveness impairs apoptosis via the BMPRII-ALK1-Bcl-xL pathway in PAH. We suggest Bcl-xL as a potential biomarker and druggable target. This work was supported by a fellowship (awarded to MTN) from the Department of Health via the NIHR Comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London, Heptagon Life Science Proof of Concept Fund (grant KCL24 to MTN), the Great Britain Sasakawa Foundation (grant B70 to MTN), the Royal Society (grant 43049 to MTN), the Medical Research Council (grant G900865 to RCT, MTN and NWM) and the University of Bradford (grants 003200, 66006/001NAS and DH005 to MTN). NS and MYB were supported by scholarships from the Commonwealth Scholarship Commission, UK and Scientific and Technological Research Council of Turkey (TUBITAK), respectively. The full-text of this article will be released for public view at the end of the publisher embargo on 28 Feb 2020. 2019-03-08T12:24:31Z 2019-03-08T12:24:31Z 2019-07 2019-02-18 2019-02-27 2020-02-28 Article Accepted manuscript Chowdhury HM, Sharmin N, Yuzbasioglu Baran M et al (2019) BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH). Human Molecular Genetics. 28(13): 2161-2173. http://hdl.handle.net/10454/16885 en https://doi.org/10.1093/hmg/ddz047 © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The definitive publisher-authenticated version is available online at: https://doi.org/10.1093/hmg/ddz047. |
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Pulmonary Arterial Hypertension (PAH) Bone morphogenetic protein (BMPRII) BMPRII deficiency Apoptosis |
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Pulmonary Arterial Hypertension (PAH) Bone morphogenetic protein (BMPRII) BMPRII deficiency Apoptosis Chowdhury, H.M. Sharmin, N. Yuzbasioglu Baran, M. Long, L. Morrell, N.W. Trembath, R.C. Nasim, Md. Talat BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH) |
description |
Yes === Pulmonary Arterial Hypertension (PAH) is a devastating cardiovascular disorder characterised by the remodelling of pre-capillary pulmonary arteries. The vascular remodelling observed in PAH patients results from excessive proliferation and apoptosis resistance of pulmonary arterial smooth muscle (PASMCs) and endothelial cells (PAECs). We have previously demonstrated that mutations in the type II receptor for bone morphogenetic protein (BMPRII) underlie the majority of the familial and inherited forms of the disease. We have further demonstrated that BMPRII deficiency promotes excessive proliferation and attenuates apoptosis in PASMCs, but the underlying mechanisms remain unclear. The major objective of this study is to investigate how BMPRII deficiency impairs apoptosis in PAH. Using multidisciplinary approaches, we demonstrate that deficiency in the expression of BMPRII impairs apoptosis by modulating the alternative splicing of the apoptotic regulator, Bcl-x (B-cell lymphoma X) transcripts: a finding observed in circulating leukocytes and lungs of PAH subjects, hypoxia-induced PAH rat lungs as well as in PASMCs and PAECs. BMPRII deficiency elicits cell specific effects: promoting the expression of Bcl-xL transcripts in PASMCs whilst inhibiting it in ECs, thus exerting differential apoptotic effects in these cells. The pro-survival effect of BMPRII receptor is mediated through the activin receptor like kinase 1 (ALK1) but not the ALK3 receptor. Finally, we show that BMPRII interacts with the ALK1 receptor and pathogenic mutations in the BMPR2 gene abolish this interaction. Taken together, dysfunctional BMPRII responsiveness impairs apoptosis via the BMPRII-ALK1-Bcl-xL pathway in PAH. We suggest Bcl-xL as a potential biomarker and druggable target. === This work was supported by a fellowship (awarded to MTN) from the Department of Health via the NIHR Comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London, Heptagon Life Science Proof of Concept Fund (grant KCL24 to MTN), the Great Britain Sasakawa Foundation (grant B70 to MTN), the Royal Society (grant 43049 to MTN), the Medical Research Council (grant G900865 to RCT, MTN and NWM) and the University of Bradford (grants 003200, 66006/001NAS and DH005 to MTN). NS and MYB were supported by scholarships from the Commonwealth Scholarship Commission, UK and Scientific and Technological Research Council of Turkey (TUBITAK), respectively. === The full-text of this article will be released for public view at the end of the publisher embargo on 28 Feb 2020. |
author |
Chowdhury, H.M. Sharmin, N. Yuzbasioglu Baran, M. Long, L. Morrell, N.W. Trembath, R.C. Nasim, Md. Talat |
author_facet |
Chowdhury, H.M. Sharmin, N. Yuzbasioglu Baran, M. Long, L. Morrell, N.W. Trembath, R.C. Nasim, Md. Talat |
author_sort |
Chowdhury, H.M. |
title |
BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH) |
title_short |
BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH) |
title_full |
BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH) |
title_fullStr |
BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH) |
title_full_unstemmed |
BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension (PAH) |
title_sort |
bmprii deficiency impairs apoptosis via the bmprii-alk1-bclx-mediated pathway in pulmonary arterial hypertension (pah) |
publishDate |
2019 |
url |
http://hdl.handle.net/10454/16885 |
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