Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension

• Published in: The Journal of pathology Vol. 249; no. 3; pp. 356 - 367
• Main Authors: Gomez‐Puerto, Maria Catalina, Zuijen, Iris, Huang, Christopher JZ, Szulcek, Robert, Pan, Xiaoke, Dinther, Maarten AH, Kurakula, Kondababu, Wiesmeijer, Catharina C, Goumans, Marie‐Jose, Bogaard, Harm‐Jan, Morrell, Nicholas W, Rana, Amer Ahmed, ten Dijke, Peter
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.11.2019; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Arterial Pressure; Autophagy; Blood pressure; BMPR2; BMPR2+/− iPSC‐ECs; Bone morphogenetic protein receptor type II; Bone Morphogenetic Protein Receptors, Type II - genetics; Bone Morphogenetic Protein Receptors, Type II - metabolism; Bone morphogenetic proteins; Cell Line; Cytokines; Cytokines - metabolism; Degradation; Disease Models, Animal; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Environmental factors; Female; Fluctuations; Heart diseases; Heterozygosity; Heterozygote; human pulmonary artery endothelial cells (PAECs); human pulmonary artery smooth muscle cells (PASMCs); Humans; Hypertension; Inflammation; Inflammation Mediators - metabolism; Lysosomes; Lysosomes - metabolism; Lysosomes - pathology; Male; Microtubule-Associated Proteins - metabolism; Microvasculature; Middle Aged; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Muscle, Smooth, Vascular - physiopathology; Muscles; Mutation; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Original Paper; Original Papers; Pathology; Phagocytosis; Proteolysis; pulmonary arterial hypertension (PAH); Pulmonary Arterial Hypertension - metabolism; Pulmonary Arterial Hypertension - pathology; Pulmonary Arterial Hypertension - physiopathology; Pulmonary arteries; Pulmonary artery; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Pulmonary Artery - physiopathology; Pulmonary hypertension; Rats; Signal Transduction; Smooth muscle; Young Adult; human pulmonary artery smooth muscle cells (PASMCs); BMPR2; BMPR2+/− iPSC-ECs; autophagy; human pulmonary artery endothelial cells (PAECs); inflammation; pulmonary arterial hypertension (PAH)
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.5322

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. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.