Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension
Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension
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DOI：
10.1038/hr.2010.16
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发表时间：
2010-05-01
影响因子：
5.4
通讯作者：
Makino, Hirofumi
中科院分区：
文献类型：
--
作者：
Yamanaka, Ryutaro;Otsuka, Fumio;Makino, Hirofumi
最近的遗传学研究揭示了家族性和特发性肺动脉高压（PAH）与骨形态发生蛋白II型受体（BMPRII）的种系突变之间的联系。PAH的病理学特征是由于肺动脉平滑肌细胞（PASMC）过度增殖导致的肺动脉重塑。尽管内皮损伤增加和PASMC增殖抑制受损对于PAH的细胞发病机制都是至关重要的，但PAH的详细分子机制尚未阐明。在本研究中，我们研究了BMP系统和其他与PAH相关的血管活性因子（包括内皮素（ET），血管紧张素II（Ang II）和醛固酮）在从特发性和继发性PAH肺分离的PASMCs的有丝分裂活动中的作用。ET 1和醛固酮刺激PASMC增殖的特发性PAH比继发性PAH更有效，而血管紧张素II和ET 3未能激活有丝分裂的PASMC细胞类型。ET 1和醛固酮的作用分别被ET A/B型受体（ETA/BR）拮抗剂波生坦和选择性盐皮质激素受体（MR）阻断剂依普利酮阻断。在检查的BMP配体中，BMP-2和BMP-7，而不是BMP-4或BMP-6，显著增加了两种PASMC细胞类型中的细胞有丝分裂。值得注意的是，ET 1和醛固酮诱导的有丝分裂和有丝分裂原活化蛋白激酶磷酸化的存在下，BMP-2和BMP-7的PASMCs分离自特发性PAH显着增加，虽然添加剂的效果没有观察到PASMCs分离自继发性PAH。抑制细胞外信号调节激酶1（ERK 1）/ERK 2信号转导抑制基础，ET 1和醛固酮诱导的PASMC有丝分裂比应激活化蛋白激酶/c-Jun NH 2-末端激酶抑制更有力。考虑到BMP-2和BMP-7上调ETA/BR和MR表达以及BMP-2降低从特发性PAH分离的PASMC中的11 β HSD 2（11 β-羟基类固醇脱氢酶2型）水平的事实，BMPR-Smad信号传导可能在放大PAH肺的PASMC中的ETA/BR和/或MR-ERK信号传导中具有关键作用。总之，BMP和ET和/或MR系统之间的功能联系可能参与PASMC有丝分裂的进展，最终导致临床PAH的发展。高血压研究（2010）33，435-445; doi：10.1038/hr.2010.16;在线发表2010年2月26日
Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1- and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1- and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11 beta HSD2 (11 beta-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH. Hypertension Research (2010) 33, 435-445; doi: 10.1038/hr.2010.16; published online 26 February 2010