Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension
Identifieur interne : 000A42 ( Main/Merge ); précédent : 000A41; suivant : 000A43Autophagy 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
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DOI: 10.1002/path.5322
PubMed: 31257577
PubMed Central: 6852495
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<author><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>
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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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