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The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations.

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Dunmore, Benjamin J 
Drake, Kylie M 
Upton, Paul D 
Toshner, Mark R 
Aldred, Micheala A 


Pulmonary arterial hypertension (PAH) is characterized by dysregulated pulmonary artery endothelial cell (PAEC) proliferation, apoptosis and permeability. Loss-of-function mutations in the bone morphogenetic protein receptor type-II (BMPR-II) are the most common cause of heritable PAH, usually resulting in haploinsufficiency. We previously showed that BMPR-II expression is regulated via a lysosomal degradative pathway. Here, we show that the antimalarial drug, chloroquine, markedly increased cell surface expression of BMPR-II protein independent of transcription in PAECs. Inhibition of protein synthesis experiments revealed a rapid turnover of cell surface BMPR-II, which was inhibited by chloroquine treatment. Chloroquine enhanced PAEC expression of BMPR-II following siRNA knockdown of the BMPR-II transcript. Using blood outgrowth endothelial cells (BOECs), we confirmed that signalling in response to the endothelial BMPR-II ligand, BMP9, is compromised in BOECs from patients harbouring BMPR-II mutations, and in BMPR-II mutant PAECs. Chloroquine significantly increased gene expression of BMP9-BMPR-II signalling targets Id1, miR21 and miR27a in both mutant BMPR-II PAECs and BOECs. These findings provide support for the restoration of cell surface BMPR-II with agents such as chloroquine as a potential therapeutic approach for heritable PAH.



Bone Morphogenetic Protein Receptors, Type II, Cell Line, Cell Membrane, Cells, Cultured, Chloroquine, Endothelial Cells, Familial Primary Pulmonary Hypertension, Growth Differentiation Factor 2, Growth Differentiation Factors, Humans, Hypertension, Pulmonary, Lysosomes, Mutation, Pulmonary Artery, RNA, Small Interfering, Signal Transduction, Smad Proteins, Transcription, Genetic

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Hum Mol Genet

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Oxford University Press (OUP)
Medical Research Council (G1000847)
Medical Research Council (G0800784)