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PMID: 16195541 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Serotonin-induced growth of pulmonary artery smooth muscle requires activation of phosphatidylinositol 3-kinase/serine-threonine protein kinase B/mammalian target of rapamycin/p70 ribosomal S6 kinase 1.

American journal of respiratory cell and molecular biology ·Vol. 34 ·No. 2 ·2006-02-00 ·Pages 182-91

Liu Y, Fanburg BL

Abstract

We have previously found that both mitogen-activated protein kinase (MAPK)- and Rho kinase (ROCK)-related signaling pathways are necessary for the induction of pulmonary artery smooth muscle cell (SMC) proliferation by serotonin (5-hydroxytryptamine [5-HT]). In the present study, we investigated the possible additional participation of a phosphatidylinositol 3-kinase (PI3K)/serine-threonine protein kinase B (Akt)/mammalian target of rapamycin (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 ROCK 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 small interfering RNA 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, 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 reduced nicotinamide adenine dinucleotide phosphate oxidase inhibitor, diphenyleneiodonium, and the 5-HT2 receptor antagonists ketanserin and mianserin, but not by the 5-HT serotonin transporter or 5-HT 1B/1D receptor antagonists. We conclude from these studies that a parallel PI3K- and reactive oxygen species-dependent Akt/mTOR/S6K1 pathway participates independently from MAPK and Rho/ROCK in the mitogenic effect of 5-HT on pulmonary artery SMCs. 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 serotonin transporter at the cell surface.

MeSH Terms
Animals Antioxidants/pharmacology Cattle Cell Proliferation/drug effects Cells, Cultured Enzyme Activation Enzyme Inhibitors/pharmacology Enzymes/drug effects,metabolism Intracellular Signaling Peptides and Proteins Muscle, Smooth, Vascular/drug effects,growth & development,metabolism Oncogene Protein v-akt/drug effects,metabolism Phosphatidylinositol 3-Kinases/drug effects,metabolism Phosphorylation/drug effects Protein Kinases/metabolism Protein Serine-Threonine Kinases/drug effects,metabolism Proto-Oncogene Proteins c-akt/drug effects,metabolism Pulmonary Artery/cytology,drug effects,metabolism Reactive Oxygen Species/metabolism Receptor, Serotonin, 5-HT2A/drug effects,metabolism Ribosomal Protein S6 Kinases, 90-kDa/drug effects,metabolism Serotonin/pharmacology Serotonin 5-HT2 Receptor Antagonists TOR Serine-Threonine Kinases rho-Associated Kinases
Chemicals
Antioxidants Enzyme Inhibitors Enzymes Intracellular Signaling Peptides and Proteins Reactive Oxygen Species Receptor, Serotonin, 5-HT2A Serotonin 5-HT2 Receptor Antagonists Serotonin Protein Kinases Oncogene Protein v-akt Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinases, 90-kDa TOR Serine-Threonine Kinases rho-Associated Kinases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Liu Yinglin
Pulmonary, Critical Care, and Sleep Division, Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111, USA.
Fanburg Barry L
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Article Info
Journal
American journal of respiratory cell and molecular biology
Abbr.
Am J Respir Cell Mol Biol
ISSN
1044-1549
DOI
10.1165/rcmb.2005-0163OC
Published
2006-02-00
Epub
2005-00-29
Pages
182-91
Language
English
Region
United States
NLM ID
8917225
PMCID
PMC2644181
Subset
IM
Grants
NHLBI NIH HHS · HL32723 · United States
External Links
PubMed source DOI: 10.1165/rcmb.2005-0163OC PMC Full Text View journal details
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