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

Hum Mol Genet. 2013 Sep 15;22(18):3667-79. doi: 10.1093/hmg/ddt216. Epub 2013 May 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein Receptors, Type II / genetics*
  • Bone Morphogenetic Protein Receptors, Type II / metabolism*
  • Cell Line
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Chloroquine / pharmacology*
  • Chloroquine / therapeutic use
  • Endothelial Cells / metabolism*
  • Familial Primary Pulmonary Hypertension
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors / metabolism*
  • Humans
  • Hypertension, Pulmonary / drug therapy
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / metabolism
  • Lysosomes / metabolism
  • Mutation
  • Pulmonary Artery / cytology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism
  • Transcription, Genetic


  • GDF2 protein, human
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors
  • RNA, Small Interfering
  • Smad Proteins
  • Chloroquine
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II