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Published ahead of print on September 29, 2005, doi:10.1165/rcmb.2005-0163OC

Am. J. Respir. Cell Mol. Biol., Volume 34, Number 2, February 2006, 182-191

A more recent version of this article appeared on February 1, 2006
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Submitted on May 2, 2005
Revised on September 28, 2005

Serotonin-induced Growth of Pulmonary Artery Smooth Muscle Requires Activation of PI3K/Akt/S6K1

Yinglin Liu1 and Barry L Fanburg1*

1 Department of Medicine, Pulmonary, Critical Care and Sleep Division, Tufts-New England Medical Center, Tupper Research Institute, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: bfanburg{at}tufts-nemc.org.

We previously found that both MAPK- and Rho kinase (ROCK)-related signaling pathways are necessary for the induction of pulmonary artery smooth muscle cell (PASMC) proliferation by serotonin (5-HT). Presently we investigated the possible additional participation of a phosphoinositide 3-kinase (PI3K)/Akt/mTOR/p70 ribosomal S6 kinase (S6K1) pathway in this growth response. We found transient activation of Akt (Ser473) and more prolonged activation of S6K1 by 5-HT. Inhibition of PI3K with Wortmannin and LY294002 completely blocked these activations, but not that of MAPK or the Rho kinase substrate myosin phosphatase targeting subunit. Similarly, inhibition of MAPK and ROCK failed to block the Akt activation. Inhibition of Akt with NL-71-101 and downregulation of Akt expression with Akt siRNA blocked 5-HT-induced S6K1 phosphorylation. Wortmannin, LY294002 and NL-71-101 dose dependently inhibited 5-HT-induced SMC proliferation. 5-HT stimulated mTOR phosphorylation and the mTOR inhibitor, rapamycin, blocked activations of S6K1 and S6 ribosomal protein (S6) and inhibited 5-HT-induced SMC proliferation. Akt phosphorylation and cell proliferation were also blocked by the antioxidants, N-acetyl-l-cysteine, Ginko biloba 501 and Tiron; the NADPH oxidase inhibitor, diphenyleneiodonium; and the 5-HT2 receptor antagonist ketanserin and mianserin, but not by the 5-HT transporter (SERT) and 5-HT 1B/1D receptor antagonists. We conclude from these studies that a parallel PI3K- and ROS-dependent Akt/mTOR/S6K1 pathway participates independently from MAPK and Rho/ROCK for the mitogenic effect of 5-HT on PASMCs. From these and other studies we postulate that independent signaling pathways leading to 5-HT-induced SMC proliferation are initiated through multiple 5-HT receptors and SERT at the cell surface.




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