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.

中文翻译：

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自噬有助于BMP 2型受体降解和肺动脉高压的发展。

肺动脉高压（PAH）的特征是平均肺动脉压升高，几乎总是导致右心衰竭和过早死亡。超过70％的家族性PAH和20％的特发性PAH患者携带2型骨形态发生蛋白（BMP）2型受体（BMPR2）的杂合突变。但是，BMPR2的渗透率不完全突变表明其他遗传和环境因素也导致了这种疾病。在当前的研究中，我们调查自噬在肺血管细胞中BMPR2降解中的作用。我们证明内源性BMPR2通过原代人肺动脉内皮细胞（PAECs）和平滑肌细胞（PASMCs）中的溶酶体降解：两种在疾病病理中起关键作用的细胞类型。通过优雅的HaloTag系统，我们显示了溶酶体降解的阻滞导致质膜上BMPR2水平的增加。此外，自噬的药理或基因操作使我们得出结论，自噬激活有助于BMPR2降解。必须进一步研究自噬在BMPR2降解中的作用是直接的还是通过内吞途径的调节。有趣的是，使用iPSC衍生的内皮细胞模型，我们的发现表明单独的BMPR2杂合度足以引起自噬通量的增加。除BMPR2杂合性外，促炎细胞因子还有助于增强肺血管细胞的自噬。此外，我们证明了大鼠诱发的PAH肺切片中微管相关蛋白1轻链3 beta（MAP1LC3B）的水平增加。因此，来自末期特发性PAH患者的肺微血管内皮细胞（MVEC）表现出较高的自噬通量。我们的发现支持一种模型，其中PAH患者自噬通量的增加有助于BMPR2水平的更大降低。总而言之，这项研究阐明了BMPR2降解的基本机制，并强调了自噬在PAH中的关键作用。©2019作者。该病理学杂志代表英国和爱尔兰的病理学学会出版由John Wiley父子有限公司。