{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:54:15Z","timestamp":1790078055022,"version":"4.0.1"},"reference-count":53,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,8,27]],"date-time":"2019-08-27T00:00:00Z","timestamp":1566864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>BMPR2<\/jats:italic>\n                    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\u2010derived endothelial cell model, our findings indicate that\n                    <jats:italic>BMPR2<\/jats:italic>\n                    heterozygosity alone is sufficient to cause an increased autophagic flux. Besides\n                    <jats:italic>BMPR2<\/jats:italic>\n                    heterozygosity, pro\u2010inflammatory cytokines also contribute to an augmented autophagy in lung vascular cells. Furthermore, we demonstrate an increase in microtubule\u2010associated protein 1 light chain 3 beta (MAP1LC3B) levels in lung sections from PAH induced in rats. Accordingly, pulmonary microvascular endothelial cells (MVECs) from end\u2010stage 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. \u00a9 2019 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.5322","type":"journal-article","created":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T03:38:56Z","timestamp":1561952336000},"page":"356-367","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Autophagy contributes to BMP type 2 receptor degradation and\u00a0development of pulmonary arterial hypertension"],"prefix":"10.1002","volume":"249","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5362-9780","authenticated-orcid":false,"given":"Maria Catalina","family":"Gomez\u2010Puerto","sequence":"first","affiliation":[{"name":"Department of Cell and Chemical Biology and Oncode Institute Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"van Zuijen","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology and Oncode Institute Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher JZ","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Szulcek","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology and Oncode Institute Leiden University Medical Center  Leiden The Netherlands"},{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pulmonary Medicine Amsterdam Cardiovascular Sciences  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoke","family":"Pan","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pulmonary Medicine Amsterdam Cardiovascular Sciences  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9451-8884","authenticated-orcid":false,"given":"Maarten AH","family":"van Dinther","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology and Oncode Institute Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kondababu","family":"Kurakula","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology and Oncode Institute Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharina C","family":"Wiesmeijer","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology and Oncode Institute Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9344-6746","authenticated-orcid":false,"given":"Marie\u2010Jose","family":"Goumans","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology and Oncode Institute Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harm\u2010Jan","family":"Bogaard","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pulmonary Medicine Amsterdam Cardiovascular Sciences  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas 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