BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGF-TAK1-MAPK pathways in PAH
BMPR-II deficiency elicits pro-proliferative and anti-apoptotic responses through the activation of TGF-TAK1-MAPK pathways in PAH
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DOI：
10.1093/hmg/dds073
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发表时间：
2012-06-01
影响因子：
3.5
通讯作者：
Trembath, Richard C.
中科院分区：
文献类型：
--
作者：
Nasim, Md Talat;Ogo, Takeshi;Trembath, Richard C.
肺动脉高压(PAH)是一种与肺动脉平滑肌细胞(PASMCs)增殖增强和凋亡抑制相关的心血管疾病。骨形态发生蛋白II型受体(BMPR2)杂合突变是大多数遗传性和家族性PAH的基础。转化生长因子(TGF)途径在人和实验性PAH模型中均被激活。然而，这些因素如何在PAH中发挥促增殖和抗凋亡反应仍不清楚。利用来自基因敲除小鼠的小鼠原代PASMC，我们证明了BMPR-II功能障碍促进了小母亲通过转化生长因子相关激酶1(TAK1)激活不依赖于有丝分裂原激活的蛋白激酶(MAPK)通路，从而导致促增殖和抗凋亡反应。抑制TAK1-MAPK轴可以挽救这些细胞的异常增殖和凋亡。在低氧和野百合碱诱导的PAH大鼠模型中，bmpr2转录水平降低，本研究进一步表明，随着TAK1蛋白表达和磷酸化的上调，肺组织中的转化生长因子-MAPK轴被激活。在体外细胞检测中，TAK1抑制BMP反应性报告活性，并与BMPR-II受体相互作用。在PAH患者中观察到致病性BMPR2突变时，这种相互作用大大减少。综上所述，这些数据表明，功能失调的BMPR-II反应增强了转化生长因子-TAK1-MAPK信号，从而改变了细胞凋亡与增殖的比率。该轴可能成为治疗PAH的潜在靶点。
Pulmonary arterial hypertension (PAH) is a cardiovascular disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR2) underlie the majority of the inherited and familial forms of PAH. The transforming growth factor (TGF) pathway is activated in both human and experimental models of PAH. However, how these factors exert pro-proliferative and anti-apoptotic responses in PAH remains unclear. Using mouse primary PASMCs derived from knock-in mice, we demonstrated that BMPR-II dysfunction promotes the activation of small mothers against decapentaplegia-independent mitogen-activated protein kinase (MAPK) pathways via TGF-associated kinase 1 (TAK1), resulting in a pro-proliferative and anti-apoptotic response. Inhibition of the TAK1-MAPK axis rescues abnormal proliferation and apoptosis in these cells. In both hypoxia and monocrotaline-induced PAH rat models, which display reduced levels of bmpr2 transcripts, this study further indicates that the TGF-MAPK axis is activated in lungs following elevation of both expression and phosphorylation of the TAK1 protein. In ex vivo cell-based assays, TAK1 inhibits BMP-responsive reporter activity and interacts with BMPR-II receptor. In the presence of pathogenic BMPR2 mutations observed in PAH patients, this interaction is greatly reduced. Taken together, these data suggest dysfunctional BMPR-II responsiveness intensifies TGF-TAK1-MAPK signalling and thus alters the ratio of apoptosis to proliferation. This axis may be a potential therapeutic target in PAH.