TY - JOUR
T1 - Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension
AU - Gomez-Puerto, Maria Catalina
AU - van Zuijen, Iris
AU - Huang, Christopher J. Z.
AU - Szulcek, Robert
AU - Pan, Xiaoke
AU - van Dinther, Maarten A. H.
AU - Kurakula, Kondababu
AU - Wiesmeijer, Catharina C.
AU - Goumans, Marie-Jose
AU - Bogaard, Harm-Jan
AU - Morrell, Nicholas W.
AU - Rana, Amer Ahmed
AU - ten Dijke, Peter
N1 - Funding Information: We would like to thank Professor Fulvio Reggiori and Professor Geir Bjørkøy for their valuable discussions. The research in our laboratory is supported by The Netherlands Cardiovascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, The Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-PHAEDRA) and Cancer Genomics Centre Netherlands (to PTD). MCGP, RS, and KK were supported by CVON-PHAEDRA. We also acknowledge support for KK by the Dutch Lung Foundation (Longfonds), grant number 5.2.17.198J0. Publisher Copyright: © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Pulmonary arterial hypertension (PAH) is characterised by an increase in mean pulmonary arterial pressure which almost invariably leads to right heart failure and premature death. More than 70% of familial PAH and 20% of idiopathic PAH patients carry heterozygous mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2). However, the incomplete penetrance of BMPR2 mutations suggests that other genetic and environmental factors contribute to the disease. In the current study, we investigate the contribution of autophagy in the degradation of BMPR2 in pulmonary vascular cells. We demonstrate that endogenous BMPR2 is degraded through the lysosome in primary human pulmonary artery endothelial (PAECs) and smooth muscle cells (PASMCs): two cell types that play a key role in the pathology of the disease. By means of an elegant HaloTag system, we show that a block in lysosomal degradation leads to increased levels of BMPR2 at the plasma membrane. In addition, pharmacological or genetic manipulations of autophagy allow us to conclude that autophagy activation contributes to BMPR2 degradation. It has to be further investigated whether the role of autophagy in the degradation of BMPR2 is direct or through the modulation of the endocytic pathway. Interestingly, using an iPSC-derived endothelial cell model, our findings indicate that BMPR2 heterozygosity alone is sufficient to cause an increased autophagic flux. Besides BMPR2 heterozygosity, pro-inflammatory cytokines also contribute to an augmented autophagy in lung vascular cells. Furthermore, we demonstrate an increase in microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) levels in lung sections from PAH induced in rats. Accordingly, pulmonary microvascular endothelial cells (MVECs) from end-stage idiopathic PAH patients present an elevated autophagic flux. Our findings support a model in which an increased autophagic flux in PAH patients contributes to a greater decrease in BMPR2 levels. Altogether, this study sheds light on the basic mechanisms of BMPR2 degradation and highlights a crucial role for autophagy in PAH.
AB - Pulmonary arterial hypertension (PAH) is characterised by an increase in mean pulmonary arterial pressure which almost invariably leads to right heart failure and premature death. More than 70% of familial PAH and 20% of idiopathic PAH patients carry heterozygous mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2). However, the incomplete penetrance of BMPR2 mutations suggests that other genetic and environmental factors contribute to the disease. In the current study, we investigate the contribution of autophagy in the degradation of BMPR2 in pulmonary vascular cells. We demonstrate that endogenous BMPR2 is degraded through the lysosome in primary human pulmonary artery endothelial (PAECs) and smooth muscle cells (PASMCs): two cell types that play a key role in the pathology of the disease. By means of an elegant HaloTag system, we show that a block in lysosomal degradation leads to increased levels of BMPR2 at the plasma membrane. In addition, pharmacological or genetic manipulations of autophagy allow us to conclude that autophagy activation contributes to BMPR2 degradation. It has to be further investigated whether the role of autophagy in the degradation of BMPR2 is direct or through the modulation of the endocytic pathway. Interestingly, using an iPSC-derived endothelial cell model, our findings indicate that BMPR2 heterozygosity alone is sufficient to cause an increased autophagic flux. Besides BMPR2 heterozygosity, pro-inflammatory cytokines also contribute to an augmented autophagy in lung vascular cells. Furthermore, we demonstrate an increase in microtubule-associated protein 1 light chain 3 beta (MAP1LC3B) levels in lung sections from PAH induced in rats. Accordingly, pulmonary microvascular endothelial cells (MVECs) from end-stage idiopathic PAH patients present an elevated autophagic flux. Our findings support a model in which an increased autophagic flux in PAH patients contributes to a greater decrease in BMPR2 levels. Altogether, this study sheds light on the basic mechanisms of BMPR2 degradation and highlights a crucial role for autophagy in PAH.
KW - BMPR2
KW - BMPR2 iPSC-ECs
KW - autophagy
KW - human pulmonary artery endothelial cells (PAECs)
KW - human pulmonary artery smooth muscle cells (PASMCs)
KW - inflammation
KW - pulmonary arterial hypertension (PAH)
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85071272239&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31257577
U2 - https://doi.org/10.1002/path.5322
DO - https://doi.org/10.1002/path.5322
M3 - Article
C2 - 31257577
SN - 0022-3417
VL - 249
SP - 356
EP - 367
JO - Journal of pathology
JF - Journal of pathology
IS - 3
ER -