Serotonin induces Rho/ROCK-dependent activation of Smads 1/5/8 in pulmonary artery smooth muscle cells
Serotonin induces Rho/ROCK-dependent activation of Smads 1/5/8 in pulmonary artery smooth muscle cells
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DOI：
10.1096/fj.08-127910
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发表时间：
2009-07-01
期刊：
影响因子：
4.8
通讯作者：
Fanburg, Barry L.
中科院分区：
文献类型：
--
作者：
Liu, Yinglin;Ren, Wenying;Fanburg, Barry L.
血清素 (5-HT) 会刺激肺动脉平滑肌细胞增殖，并与肺动脉高压 (PAH) 相关。骨形态发生蛋白受体 2 (BMPR2) 突变同样与 PAH 相关。然而，5-HT 和 BMPR 信号之间可能存在的串扰仍不清楚。我们在此报告，5-HT 激活牛和人肺动脉平滑肌细胞 (SMC) 中的 Smads 1/5/8，并导致这些 Smads 从细胞质易位到细胞核。 DN BMPR1A 阻断 5-HT 对 Smads 1/5/8 的 5-HT 激活，而 BMPR1A 过表达则增强这种激活。 5-HT 对 Smads 的激活是通过 5-HT 1B/1D 受体发生的，因为它被抑制剂 GR 55562 阻断，但不受 5-HT 转运蛋白和多种 5-HT 受体抑制剂的影响。 5-HT 对 Smad 的激活依赖于 Rho/Rho 激酶信号传导，因为它被 Y27632 阻断，但不受 PI3K 或 MAPK 抑制剂的影响。用 BMPR1A 转染细胞并将 BMP 受体与 BMP-2 连接也激活这些 SMC 的 GTP-Rho A，而 DN BMPR1A 则阻断该激活。 5-HT 刺激 BMPR1A 丝氨酸/苏氨酸磷酸化增加，支持 SMC 中 5-HT 激活 BMPR1A。用微渗输液泵将 5-HT 输注到小鼠体内，引起肺组织中 Smads 1/5/8 的激活，证明了体内效果。这些研究支持一个独特的概念，即 5-HT 反式激活丝氨酸激酶受体 BMPR 1A，从而通过肺动脉 SMC 中的 Rho 和 Rho 激酶激活 Smads 1/5/8。 Rho 和 Rho 激酶也参与 BMP 对 Smads 的激活。-Liu, Y., Ren, W., Warburton, R., Toksoz, D., Fanburg, B. L. 5-羟色胺诱导肺动脉平滑肌细胞中 Smads 1/5/8 的 Rho/ROCK 依赖性激活。 FASEB J. 23, 2299-2306 (2009)
Serotonin (5-HT) stimulates pulmonary artery smooth muscle cell proliferation and has been associated with pulmonary arterial hypertension (PAH). Bone morphogenetic protein receptor 2 (BMPR2) mutations similarly have been linked to PAH. However, possible crosstalk between 5-HT and BMPR signaling remains poorly characterized. We report here that 5-HT activates Smads 1/5/8 in bovine and human pulmonary artery smooth muscle cells (SMCs) and causes translocation of these Smads from cytoplasm to the nucleus. DN BMPR1A blocked 5-HT activation of Smads 1/5/8 by 5-HT and BMPR1A overexpression enhanced it. Activation of Smads by 5-HT occurred through the 5-HT 1B/1D receptor as it was blocked with the inhibitor GR 55562 but unaffected by inhibitors of the 5-HT transporter and a variety of 5-HT receptors. Activation of the Smads by 5-HT depended on Rho/Rho kinase signaling as it was blocked by Y27632, but unaffected by inhibitors of PI3K or MAPK. Transfection of cells with BMPR1A and ligation of the BMP receptor with BMP-2 also activated GTP-Rho A of these SMCs, while DN BMPR1A blocked the activation. 5-HT stimulated an increase in serine/threonine phosphorylation of BMPR1A, supporting the activation of BMPR1A by 5-HT in SMCs. Infusion of 5-HT into mice with miniosmotic infusion pumps caused activation of Smads 1/5/8 in lung tissue, demonstrating the effect in vivo. The studies support a unique concept that 5-HT trans-activates the serine kinase receptor, BMPR 1A, to activate Smads 1/5/8 via Rho and Rho kinase in pulmonary artery SMCs. Rho and Rho kinase also participate in the activation of Smads by BMP.-Liu, Y., Ren, W., Warburton, R., Toksoz, D., Fanburg, B. L. Serotonin induces Rho/ROCK-dependent activation of Smads 1/5/8 in pulmonary artery smooth muscle cells. FASEB J. 23, 2299-2306 (2009)