BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension.

Autor:	Chowdhury HM; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom., Sharmin N; School of Pharmacy and Medical Sciences, University of Bradford, Bradford, United Kingdom.; Department of Pharmaceutical Technology, University of Dhaka, Dhaka, Bangladesh., Yuzbasioglu Baran M; School of Pharmacy and Medical Sciences, University of Bradford, Bradford, United Kingdom.; Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey., Long L; Division of Respiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom., Morrell NW; Division of Respiratory Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom., Trembath RC; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.; National Institute for Health Research (NIHR), Biomedical Research Centre, Guy's and St. Thomas' NHS Foundation Trust and King's College London, London, United Kingdom., Nasim MT; Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.; School of Pharmacy and Medical Sciences, University of Bradford, Bradford, United Kingdom.; National Institute for Health Research (NIHR), Biomedical Research Centre, Guy's and St. Thomas' NHS Foundation Trust and King's College London, London, United Kingdom.; Centre for Health Agricultural and Socio-economic Advancements (CHASA), Lalmonirhat, Bangladesh.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2019 Jul 01; Vol. 28 (13), pp. 2161-2173.
DOI:	10.1093/hmg/ddz047
Abstrakt:	Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disorder characterized 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 cells (PASMCs) and pulmonary arterial 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, B-cell lymphoma X (Bcl-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 while 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. (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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