The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations.
The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations.
复制标题
DOI：
10.1093/hmg/ddt216
复制
发表时间：
2013-09-15
影响因子：
3.5
通讯作者：
Morrell NW
中科院分区：
文献类型：
--
作者：
Dunmore BJ;Drake KM;Upton PD;Toshner MR;Aldred MA;Morrell NW
肺动脉高压（PAH）的特征是肺动脉内皮细胞（PAEC）增殖、凋亡和通透性失调。 II 型骨形态发生蛋白受体 (BMPR-II) 的功能丧失突变是遗传性 PAH 的最常见原因，通常会导致单倍体不足。我们之前表明 BMPR-II 表达是通过溶酶体降解途径调节的。在这里，我们发现抗疟药氯喹显着增加了 PAEC 中 BMPR-II 蛋白的细胞表面表达，且与转录无关。蛋白质合成抑制实验揭示了细胞表面 BMPR-II 的快速周转，这种周转受到氯喹处理的抑制。在 BMPR-II 转录物的 siRNA 敲低后，氯喹增强了 BMPR-II 的 PAEC 表达。使用血液生长内皮细胞 (BOEC)，我们证实，在来自携带 BMPR-II 突变的患者的 BOEC 和 BMPR-II 突变 PAEC 中，响应内皮 BMPR-II 配体 BMP9 的信号传导受到损害。氯喹显着增加突变型 BMPR-II PAEC 和 BOEC 中 BMP9-BMPR-II 信号靶标 Id1、miR21 和 miR27a 的基因表达。这些发现为使用氯喹等药物恢复细胞表面 BMPR-II 作为遗传性 PAH 的潜在治疗方法提供了支持。
Pulmonary arterial hypertension (PAH) is characterized by dysregulated pulmonary artery endothelial cell (PAEC) proliferation, apoptosis and permeability. Loss-of-function mutations in the bone morphogenetic protein receptor type-II (BMPR-II) are the most common cause of heritable PAH, usually resulting in haploinsufficiency. We previously showed that BMPR-II expression is regulated via a lysosomal degradative pathway. Here, we show that the antimalarial drug, chloroquine, markedly increased cell surface expression of BMPR-II protein independent of transcription in PAECs. Inhibition of protein synthesis experiments revealed a rapid turnover of cell surface BMPR-II, which was inhibited by chloroquine treatment. Chloroquine enhanced PAEC expression of BMPR-II following siRNA knockdown of the BMPR-II transcript. Using blood outgrowth endothelial cells (BOECs), we confirmed that signalling in response to the endothelial BMPR-II ligand, BMP9, is compromised in BOECs from patients harbouring BMPR-II mutations, and in BMPR-II mutant PAECs. Chloroquine significantly increased gene expression of BMP9-BMPR-II signalling targets Id1, miR21 and miR27a in both mutant BMPR-II PAECs and BOECs. These findings provide support for the restoration of cell surface BMPR-II with agents such as chloroquine as a potential therapeutic approach for heritable PAH.
登录
查看更多内容
影响因子：
5.3
作者：
Hartung, Anke;Bitton-Worms, Keren;Knaus, Petra
通讯作者：
Knaus, Petra
影响因子：
64.8
作者：
Davis, Brandi N.;Hilyard, Aaron C.;Hata, Akiko
通讯作者：
Hata, Akiko
影响因子：
13.3
作者：
Dalby KN;Tekedereli I;Lopez-Berestein G;Ozpolat B
通讯作者：
Ozpolat B
影响因子：
24.3
作者：
Dewachter, L.;Adnot, S.;Eddahibi, S.
通讯作者：
Eddahibi, S.
影响因子：
20.3
作者：
Liu, Dong;Wang, Jian;Li, En
通讯作者：
Li, En