Serotonin induces Rho/ROCK-dependent activation of Smads 1/5/8 in pulmonary artery smooth muscle cells

被引：33

作者：

Liu, Yinglin ^{[1
]}

Ren, Wenying ^{[1
]}

Warburton, Rod ^{[1
]}

Toksoz, Deniz ^{[1
]}

Fanburg, Barry L. ^{[1
]}

机构：

[1] Tufts Med Ctr, Pulm Crit Care & Sleep Div, Tupper Res Inst, Boston, MA 02111 USA

来源：

FASEB JOURNAL | 2009年 / 23卷 / 07期

关键词：

5-HT; BMP receptor; pulmonary hypertension; RhoA; 5-HT1B receptor; BONE MORPHOGENETIC PROTEINS; II RECEPTOR; BETA RECEPTOR; HYPERTENSION; GROWTH; KINASE; TRANSACTIVATION; MITOGENESIS; EXPRESSION; MUTATIONS;

D O I：

10.1096/fj.08-127910

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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)

引用

页码：2299 / 2306

页数：8

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