Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension
Identifieur interne : 000975 ( Pmc/Checkpoint ); précédent : 000974; suivant : 000976Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension
Auteurs : Maria Catalina Gomez-Puerto ; Iris Van Zuijen ; Christopher Jz Huang ; Robert Szulcek ; Xiaoke Pan ; Maarten Ah Van Dinther ; Kondababu Kurakula ; Catharina C. Wiesmeijer ; Marie-Jose Goumans ; Harm-Jan Bogaard ; Nicholas W. Morrell ; Amer Ahmed Rana ; Peter Ten DijkeSource :
- The Journal of Pathology [ 0022-3417 ] ; 2019.
Abstract
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
Url:
DOI: 10.1002/path.5322
PubMed: 31257577
PubMed Central: 6852495
Affiliations:
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PMC:6852495Le document en format XML
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<series><title level="j">The Journal of Pathology</title>
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<front><div type="abstract" xml:lang="en"><title>Abstract</title>
<p>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 <italic>BMPR2</italic>
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 <italic>BMPR2</italic>
heterozygosity alone is sufficient to cause an increased autophagic flux. Besides <italic>BMPR2</italic>
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. <italic>The Journal of Pathology</italic>
published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</p>
</div>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Pathol</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Pathol</journal-id>
<journal-id journal-id-type="doi">10.1002/(ISSN)1096-9896</journal-id>
<journal-id journal-id-type="publisher-id">PATH</journal-id>
<journal-title-group><journal-title>The Journal of Pathology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0022-3417</issn>
<issn pub-type="epub">1096-9896</issn>
<publisher><publisher-name>John Wiley & Sons, Ltd</publisher-name>
<publisher-loc>Chichester, UK</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31257577</article-id>
<article-id pub-id-type="pmc">6852495</article-id>
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<article-categories><subj-group subj-group-type="overline"><subject>Original Paper</subject>
</subj-group>
<subj-group subj-group-type="heading"><subject>Original Papers</subject>
</subj-group>
</article-categories>
<title-group><article-title>Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension</article-title>
<alt-title alt-title-type="right-running-head">Autophagy as a hallmark in pulmonary arterial hypertension</alt-title>
<alt-title alt-title-type="left-running-head">MC Gomez‐Puerto <italic>et al</italic>
</alt-title>
</title-group>
<contrib-group><contrib id="path5322-cr-0001" contrib-type="author" corresp="yes"><name><surname>Gomez‐Puerto</surname>
<given-names>Maria Catalina</given-names>
</name>
<contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-5362-9780</contrib-id>
<xref ref-type="aff" rid="path5322-aff-0001"><sup>1</sup>
</xref>
<address><email>m.c.gomez_puerto@lumc.nl</email>
</address>
</contrib>
<contrib id="path5322-cr-0002" contrib-type="author"><name><surname>van Zuijen</surname>
<given-names>Iris</given-names>
</name>
<xref ref-type="aff" rid="path5322-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="path5322-cr-0003" contrib-type="author"><name><surname>Huang</surname>
<given-names>Christopher JZ</given-names>
</name>
<xref ref-type="aff" rid="path5322-aff-0002"><sup>2</sup>
</xref>
</contrib>
<contrib id="path5322-cr-0004" contrib-type="author"><name><surname>Szulcek</surname>
<given-names>Robert</given-names>
</name>
<xref ref-type="aff" rid="path5322-aff-0001"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="path5322-aff-0003"><sup>3</sup>
</xref>
</contrib>
<contrib id="path5322-cr-0005" contrib-type="author"><name><surname>Pan</surname>
<given-names>Xiaoke</given-names>
</name>
<xref ref-type="aff" rid="path5322-aff-0003"><sup>3</sup>
</xref>
</contrib>
<contrib id="path5322-cr-0006" contrib-type="author"><name><surname>van Dinther</surname>
<given-names>Maarten AH</given-names>
</name>
<contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-9451-8884</contrib-id>
<xref ref-type="aff" rid="path5322-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="path5322-cr-0007" contrib-type="author"><name><surname>Kurakula</surname>
<given-names>Kondababu</given-names>
</name>
<xref ref-type="aff" rid="path5322-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="path5322-cr-0008" contrib-type="author"><name><surname>Wiesmeijer</surname>
<given-names>Catharina C</given-names>
</name>
<xref ref-type="aff" rid="path5322-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="path5322-cr-0009" contrib-type="author"><name><surname>Goumans</surname>
<given-names>Marie‐Jose</given-names>
</name>
<contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0001-9344-6746</contrib-id>
<xref ref-type="aff" rid="path5322-aff-0001"><sup>1</sup>
</xref>
</contrib>
<contrib id="path5322-cr-0010" contrib-type="author"><name><surname>Bogaard</surname>
<given-names>Harm‐Jan</given-names>
</name>
<xref ref-type="aff" rid="path5322-aff-0003"><sup>3</sup>
</xref>
</contrib>
<contrib id="path5322-cr-0011" contrib-type="author"><name><surname>Morrell</surname>
<given-names>Nicholas W</given-names>
</name>
<xref ref-type="aff" rid="path5322-aff-0002"><sup>2</sup>
</xref>
</contrib>
<contrib id="path5322-cr-0012" contrib-type="author"><name><surname>Rana</surname>
<given-names>Amer Ahmed</given-names>
</name>
<xref ref-type="aff" rid="path5322-aff-0002"><sup>2</sup>
</xref>
</contrib>
<contrib id="path5322-cr-0013" contrib-type="author"><name><surname>ten Dijke</surname>
<given-names>Peter</given-names>
</name>
<contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-7234-342X</contrib-id>
<xref ref-type="aff" rid="path5322-aff-0001"><sup>1</sup>
</xref>
</contrib>
</contrib-group>
<aff id="path5322-aff-0001"><label><sup>1</sup>
</label>
<named-content content-type="organisation-division">Department of Cell and Chemical Biology and Oncode Institute</named-content>
<institution>Leiden University Medical Center</institution>
<city>Leiden</city>
<country country="NL">The Netherlands</country>
</aff>
<aff id="path5322-aff-0002"><label><sup>2</sup>
</label>
<named-content content-type="organisation-division">Department of Medicine</named-content>
<institution>University of Cambridge</institution>
<city>Cambridge</city>
<country country="GB">UK</country>
</aff>
<aff id="path5322-aff-0003"><label><sup>3</sup>
</label>
<named-content content-type="organisation-division">Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pulmonary Medicine</named-content>
<institution>Amsterdam Cardiovascular Sciences</institution>
<city>Amsterdam</city>
<country country="NL">The Netherlands</country>
</aff>
<author-notes><corresp id="correspondenceTo"><label>*</label>
Correspondence to: MC Gomez‐Puerto, Department of Cell and Chemical Biology, Leiden University Medical Center and Oncode Institute, 2333 ZC Leiden, The Netherlands. E‐mail: <email>m.c.gomez_puerto@lumc.nl</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><day>27</day>
<month>8</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="ppub"><month>11</month>
<year>2019</year>
</pub-date>
<volume>249</volume>
<issue>3</issue>
<issue-id pub-id-type="doi">10.1002/path.v249.3</issue-id>
<fpage>356</fpage>
<lpage>367</lpage>
<history><date date-type="received"><day>25</day>
<month>11</month>
<year>2018</year>
</date>
<date date-type="rev-recd"><day>05</day>
<month>6</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>24</day>
<month>6</month>
<year>2019</year>
</date>
</history>
<permissions><pmc-comment> Copyright © 2019 Pathological Society of Great Britain and Ireland </pmc-comment>
<copyright-statement content-type="article-copyright">© 2019 The Authors. <italic>The Journal of Pathology</italic>
published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</copyright-statement>
<license license-type="creativeCommonsBy"><license-p>This is an open access article under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:href="file:PATH-249-356.pdf"></self-uri>
<abstract><title>Abstract</title>
<p>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 <italic>BMPR2</italic>
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 <italic>BMPR2</italic>
heterozygosity alone is sufficient to cause an increased autophagic flux. Besides <italic>BMPR2</italic>
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. <italic>The Journal of Pathology</italic>
published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</p>
</abstract>
<kwd-group kwd-group-type="author-generated"><kwd id="path5322-kwd-0001">autophagy</kwd>
<kwd id="path5322-kwd-0002">BMPR2</kwd>
<kwd id="path5322-kwd-0003"><italic>BMPR2</italic>
<sup><italic>+/−</italic>
</sup>
iPSC‐ECs</kwd>
<kwd id="path5322-kwd-0004">human pulmonary artery endothelial cells (PAECs)</kwd>
<kwd id="path5322-kwd-0005">human pulmonary artery smooth muscle cells (PASMCs)</kwd>
<kwd id="path5322-kwd-0006">inflammation</kwd>
<kwd id="path5322-kwd-0007">pulmonary arterial hypertension (PAH)</kwd>
</kwd-group>
<funding-group><award-group id="funding-0001"><funding-source>CVON‐PHAEDRA</funding-source>
</award-group>
<award-group id="funding-0002"><funding-source>Dutch Lung Foundation (Longfonds)</funding-source>
<award-id>5.2.17.198J0</award-id>
</award-group>
</funding-group>
<counts><fig-count count="5"></fig-count>
<table-count count="1"></table-count>
<page-count count="12"></page-count>
<word-count count="7398"></word-count>
</counts>
<custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name>
<meta-value>2.0</meta-value>
</custom-meta>
<custom-meta><meta-name>cover-date</meta-name>
<meta-value>November 2019</meta-value>
</custom-meta>
<custom-meta><meta-name>details-of-publishers-convertor</meta-name>
<meta-value>Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:13.11.2019</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><fn-group id="path5322-ntgp-0001"><fn id="path5322-note-0001"><p>No conflicts of interest were declared.</p>
</fn>
</fn-group>
</notes>
</front>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Bogaard, Harm An" sort="Bogaard, Harm An" uniqKey="Bogaard H" first="Harm-Jan" last="Bogaard">Harm-Jan Bogaard</name>
<name sortKey="Gomez Uerto, Maria Catalina" sort="Gomez Uerto, Maria Catalina" uniqKey="Gomez Uerto M" first="Maria Catalina" last="Gomez-Puerto">Maria Catalina Gomez-Puerto</name>
<name sortKey="Goumans, Marie Ose" sort="Goumans, Marie Ose" uniqKey="Goumans M" first="Marie-Jose" last="Goumans">Marie-Jose Goumans</name>
<name sortKey="Huang, Christopher Jz" sort="Huang, Christopher Jz" uniqKey="Huang C" first="Christopher Jz" last="Huang">Christopher Jz Huang</name>
<name sortKey="Kurakula, Kondababu" sort="Kurakula, Kondababu" uniqKey="Kurakula K" first="Kondababu" last="Kurakula">Kondababu Kurakula</name>
<name sortKey="Morrell, Nicholas W" sort="Morrell, Nicholas W" uniqKey="Morrell N" first="Nicholas W" last="Morrell">Nicholas W. Morrell</name>
<name sortKey="Pan, Xiaoke" sort="Pan, Xiaoke" uniqKey="Pan X" first="Xiaoke" last="Pan">Xiaoke Pan</name>
<name sortKey="Rana, Amer Ahmed" sort="Rana, Amer Ahmed" uniqKey="Rana A" first="Amer Ahmed" last="Rana">Amer Ahmed Rana</name>
<name sortKey="Szulcek, Robert" sort="Szulcek, Robert" uniqKey="Szulcek R" first="Robert" last="Szulcek">Robert Szulcek</name>
<name sortKey="Ten Dijke, Peter" sort="Ten Dijke, Peter" uniqKey="Ten Dijke P" first="Peter" last="Ten Dijke">Peter Ten Dijke</name>
<name sortKey="Van Dinther, Maarten Ah" sort="Van Dinther, Maarten Ah" uniqKey="Van Dinther M" first="Maarten Ah" last="Van Dinther">Maarten Ah Van Dinther</name>
<name sortKey="Van Zuijen, Iris" sort="Van Zuijen, Iris" uniqKey="Van Zuijen I" first="Iris" last="Van Zuijen">Iris Van Zuijen</name>
<name sortKey="Wiesmeijer, Catharina C" sort="Wiesmeijer, Catharina C" uniqKey="Wiesmeijer C" first="Catharina C" last="Wiesmeijer">Catharina C. Wiesmeijer</name>
</noCountry>
</tree>
</affiliations>
</record>
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