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(Circulation Research. 2005;97:227.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Interdependent Serotonin Transporter and Receptor Pathways Regulate S100A4/Mts1, a Gene Associated With Pulmonary Vascular Disease

Allan Lawrie, Edda Spiekerkoetter, Eliana C. Martinez, Noona Ambartsumian, W. John Sheward, Margaret R. MacLean, Anthony J. Harmar, Ann-Marie Schmidt, Eugene Lukanidin, Marlene Rabinovitch

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.

Correspondence to Dr Marlene Rabinovitch, Stanford University School of Medicine, CCSR Rm 2245B, 269 Campus Dr, Stanford, CA 93405-5162. 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 S100ß, 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-HT_1B), 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-HT_1B receptor and SERT are codependent in regulating S100A4/Mts1.

Key Words: smooth muscle cells • pulmonary hypertension • S100A4/Mts1 • serotonin • ERK1/2

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