Published online before print July 7, 2005, doi: 10.1161/01.RES.0000176025.57706.1e
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Submitted on February 28, 2005
Revised on June 14, 2005
Accepted on June 24, 2005
Interdependent Serotonin Transporter and Receptor Pathways Regulate S100A4/Mts1, a Gene Associated With Pulmonary Vascular Disease
Allan Lawrie ;
From the Department of Pediatrics (A.L., E.S., E.C.M., M.R.), Stanford University School of Medicine, Calif; the Department of Molecular Cancer Biology (N.A., E.L.), Danish Cancer Society, Copenhagen, Denmark; Division of Neuroscience (W.J.S., A.J.H.), University of Edinburgh, United Kingdom; the Institute of Biomedical and Life Sciences (M.R.M.), University of Glasgow, United Kingdom; and the Department of Physiology (A.-M.S.), Columbia University, New York. The present address for A.L. is the Division of Clinical Sciences (North), University of Sheffield, United Kingdom.
* To whom correspondence should be addressed. E-mail: marlener{at}stanford.edu.
Heightened expression of the S100 calcium-binding protein, S100A4/Mts1, is observed in pulmonary vascular disease. Loss of serotonin (5-hydroxytryptamine [5-HT]) receptors or of the serotonin transporter (SERT) attenuates pulmonary hypertension in animals, and polymorphisms causing gain of SERT function are linked to clinical pulmonary vascular disease. Because 5-HT induces release of S100
, we investigated the codependence of 5-HT receptors and SERT in regulating S100A4/Mts1 in human pulmonary artery smooth muscle cells (hPA-SMC). 5-HT elevated S100A4/Mts1 mRNA levels and increased S100A4/Mts1 protein in hPA-SMC lysates and culture media. S100A4/Mts1 in the culture media stimulated proliferation and migration of hPA-SMC in a manner dependent on the receptor for advanced glycation end products. Treatment with SB224289 (selective antagonist of 5-HT1B), fluoxetine (SERT inhibitor), SERT RNA-interference, and iproniazid (monoamine oxidase-A inhibitor), blocked 5-HT-induced S100A4/Mts1. 5-HT signaling mediated phosphorylation (p) of extracellular signal-regulated kinase 1/2 (pERK1/2), but pERK1/2 nuclear translocation depended on SERT, monoamine oxidase activity, and reactive oxygen species. Nuclear translocation of pERK1/2 was required for pGATA-4-mediated transcription of S100A4/Mts1. These data provide evidence for a mechanistic link between the 5-HT pathway and S100A4/Mts1 in pulmonary hypertension and explain how the 5-HT1B receptor and SERT are codependent in regulating S100A4/Mts1.
Key words: smooth muscle cells • pulmonary hypertension • S100A4/Mts1 • serotonin • ERK1/2 • GATA-4
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