In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and Its Target Slug.
In Pulmonary Arterial Hypertension, Reduced BMPR2 Promotes Endothelial-to-Mesenchymal Transition via HMGA1 and Its Target Slug.
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DOI：
10.1161/circulationaha.115.020617
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发表时间：
2016-05-03
期刊：
影响因子：
37.8
通讯作者：
Rabinovitch M
中科院分区：
文献类型：
--
作者：
Hopper RK;Moonen JR;Diebold I;Cao A;Rhodes CJ;Tojais NF;Hennigs JK;Gu M;Wang L;Rabinovitch M
我们先前报道了高通量RNA测序分析，确定了与对照组相比，特发性PA高血压（IPAH）患者肺动脉（PA）内皮细胞（EC）中染色质结构因子高迁移率族AT-钩1（HMGA 1）的表达增加。由于HMGA 1促进癌症中的上皮向间充质转化，我们假设HMGA 1增加可诱导PAEC向平滑肌（SM）样间充质表型（EndMT）转化，从而解释PAEC功能失调和可能的细胞对晚期IPAH特征性闭塞性重塑的贡献。我们记录了从IPAH与供体对照肺培养的PAEC中HMGA 1的增加。肺外植体的共聚焦显微镜检查将HMGA 1的增加始终定位于PA内皮，并在闭塞性和丛源性病变中鉴定出许多HMGA 1和平滑肌22 α（SM 22 α）双阳性细胞。由于在PAH中观察到骨形态发生蛋白受体（BMPR）2的表达和功能降低，我们通过siRNA减少了对照PAEC中的BMPR 2，并记录了HMGA 1蛋白的增加。与HMGA 1导致PAEC的转变一致，我们检测到PECAM-1（CD 31）减少，EndMT标志物αSMA、SM 22 α、钙调蛋白、磷酸波形蛋白和Slug增加。这种转变与纺锤体SM样形态有关，BMPR 2和HMGA 1或Slug的联合敲除在很大程度上逆转了αSMA的增加。来自EC特异性BMPR 2缺失的小鼠的肺EC显示出相似的基因和蛋白质变化。由功能障碍的BMPR 2信号传导引起的PAEC中HMGA 1的增加可以将内皮细胞转变为与PAH相关的SM样细胞。
We previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial (PA) endothelial cells (ECs) from idiopathic PA hypertension (IPAH) patients compared to controls. Since HMGA1 promotes epithelial to mesenchymal transition in cancer, we hypothesized that increased HMGA1 could induce transition of PAECs to a smooth muscle (SM)-like mesenchymal phenotype (EndMT), explaining both dysregulation of PAEC function and possible cellular contribution to the occlusive remodeling that characterizes advanced IPAH. We documented increased HMGA1 in PAECs cultured from IPAH vs. donor control lungs. Confocal microscopy of lung explants localized the increase in HMGA1 consistently to PA endothelium, and identified many cells double-positive for HMGA1 and smooth muscle 22 alpha (SM22α) in occlusive and plexogenic lesions. Since decreased expression and function of bone morphogenetic protein receptor (BMPR)2 is observed in PAH, we reduced BMPR2 by siRNA in control PAECs and documented an increase in HMGA1 protein. Consistent with transition of PAECs by HMGA1, we detected reduced PECAM-1 (CD31) and increased EndMT markers, αSMA, SM22α, calponin, phospho-vimentin and Slug. The transition was associated with spindle SM-like morphology, and the increase in αSMA was largely reversed by joint knockdown of BMPR2 and HMGA1 or Slug. Pulmonary ECs from mice with EC-specific loss of BMPR2 showed similar gene and protein changes. Increased HMGA1 in PAECs resulting from dysfunctional BMPR2 signaling can transition endothelium to SM-like cells associated with PAH.