Monocrotaline pyrrole enhanced bone morphogenetic protein 7 signaling transduced by alternative activin A receptor type 2A in pulmonary arterial smooth muscle cells
Monocrotaline pyrrole enhanced bone morphogenetic protein 7 signaling transduced by alternative activin A receptor type 2A in pulmonary arterial smooth muscle cells
复制标题
野百合碱吡咯增强肺动脉平滑肌细胞中替代激活素 A 受体 2A 型转导的骨形态发生蛋白 7 信号传导
DOI：
10.1016/j.ejphar.2019.172679
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发表时间：
2019-11-15
影响因子：
5
通讯作者：
Wu Bingxiang
中科院分区：
文献类型：
--
作者：
Sun, Na;Chen, Yiqiang;Wu Bingxiang
背景：骨形态发生蛋白7（BMP 7）表达水平升高与肺动脉高压患者预后不良相关。然而，BMP 7信号通路是否参与野百合碱（monocrotaline，MCT）诱导的肺动脉高压（pulmonary arterial hypertension，PAH）大鼠肺动脉平滑肌细胞（pulmonary arterial smooth muscle cells，PASMC）的增殖尚不清楚。此外，MCT的推定毒性代谢产物野百合碱吡咯（MCTP）可增加培养的肺动脉平滑肌细胞（PASMC）中BMP 7、增殖细胞核抗原（PCNA）和激活素A受体2A型的表达，但降低骨形态发生蛋白受体2型的表达。在PASMCs中，外源性BMP 7导致激活素A受体2型表达降低，p38 MAPK磷酸化增加和P21升高。然而，BMP 7处理导致骨形态发生蛋白2型受体敲低的PASMCs中激活素A受体2A型、p38 MAPK和PCNA的表达增加。结论：MCTP可抑制骨形态发生蛋白2型受体（BMP7）的表达，但增加活化素A受体（2A）的表达，BMP7通过优先激活活化素A受体（2A）信号轴介导PASMC增殖。
Background: Increased expression levels of bone morphogenetic protein 7 (BMP7) are associated with poor prognosis in pulmonary hypertension patients. However, whether BMP7 signaling conspire to involve in the proliferation of pulmonary artery smooth muscle cells (PASMC) underlying monocrotaline (MCT) induced pulmonary arterial hypertension (PAH) remain unclear.Methods and Results: Western blot experiments found BMP7 was increased in pulmonary arteries isolated from MCT-PAH rat. In addition, monocrotaline pyrrole (MCTP), the putative toxic metabolite of the MCT, increases the expression of BMP7, proliferating cell nuclear antigen (PCNA) and activin A receptor type 2A, but decreases bone morphogenetic protein receptor type 2 in cultured pulmonary artery smooth muscle cells (PASMC). In PASMCs, exogenous BMP7 leads to the decreasing expression of activin A receptor type 2, increasing phosphorylation of p38MAPK and elevation of P21. However, BMP7 treatment results in the increasing expression of activin A receptor type 2A, p38MAPK, and PCNA in bone morphogenetic protein receptor type 2 knockdown PASMCs. Knockdown of activin A receptor type 2A abrogated the MCTP-induced PCNA and cell cycle progression.Conclusions: MCTP treatment lead to the expression of BMP7, suppression of bone morphogenetic protein receptor type 2 but increasing expression of activin A receptor type 2A, the BMP7 mediated PASMC proliferation via preferential activation of an activin A receptor type 2A signaling axis.