Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kitaku, Okayama, Japan.
Hypertens Res. 2010 May;33(5):435-45. doi: 10.1038/hr.2010.16. Epub 2010 Feb 26.
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 11betaHSD2 (11beta-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.
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）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 的细胞发病机制都很关键，但 PAH 的详细分子机制尚未阐明。在本研究中，我们研究了与 PAH 相关的 BMP 系统和其他血管活性因子（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 肺中分离的 PASMC 的有丝分裂作用中的作用。ET1 和醛固酮刺激特发性 PAH 的 PASMC 增殖比继发性 PAH 更有效，而 Ang II 和 ET3 均不能激活两种 PASMC 细胞类型的有丝分裂。ET1 和醛固酮的作用分别被 bosentan（一种 ET 型-A/B 受体（ETA/BR）拮抗剂）和 eplerenone（一种选择性盐皮质激素受体（MR）阻滞剂）阻断。在研究的 BMP 配体中，BMP-2 和 BMP-7 但不是 BMP-4 或 BMP-6，显著增加了两种 PASMC 细胞类型的细胞有丝分裂。值得注意的是，ET1 和醛固酮诱导的有丝分裂和丝裂原激活蛋白激酶磷酸化在存在 BMP-2 和 BMP-7 的情况下在特发性 PAH 中分离的 PASMC 中显著增加，尽管在继发性 PAH 中分离的 PASMC 中没有观察到相加作用。细胞外信号调节激酶 1（ERK1）/ERK2 信号的抑制比应激激活蛋白激酶/c-Jun NH2-末端激酶抑制更有效地抑制基础、ET1 和醛固酮诱导的 PASMC 有丝分裂。鉴于 BMP-2 和 BMP-7 上调了 ETA/BR 和 MR 的表达，并且 BMP-2 降低了特发性 PAH 中分离的 PASMC 中的 11βHSD2（11β-羟类固醇脱氢酶 2）水平，BMPR-Smad 信号可能在 PAH 肺 PASMC 中的 ETA/BR 和/或 MR-ERK 信号放大中起关键作用。总之，BMP 与 ET 和/或 MR 系统之间的功能联系可能参与了 PASMC 有丝分裂的进展，最终导致临床 PAH 的发展。
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