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

doi:10.1161/01.RES.0000176025.57706.1e

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

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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 and Marlene Rabinovitch

Circulation research, Vol.97(3), pp.227-235

2005-08-05

DOI: https://doi.org/10.1161/01.RES.0000176025.57706.1e

PMID: 16002749

Abstract

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 S100β, 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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.37 Cardiology - General; 1.37.691 Pulmonary Hypertension
Web Of Science research areas: Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease
ESI research areas: Clinical Medicine

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Title: Interdependent Serotonin Transporter and Receptor Pathways Regulate S100A4/Mts1, a Gene Associated With Pulmonary Vascular Disease
Creators: 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
Edda Spiekerkoetter - 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
Eliana C Martinez - 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
Noona Ambartsumian - 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
W. John Sheward - 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
Margaret R MacLean - 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
Anthony J Harmar - 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
Ann-Marie Schmidt - 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
Eugene Lukanidin - 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
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
Publication Details: Circulation research, Vol.97(3), pp.227-235
Language: English
Resource Type: Journal article
PMID: 16002749
Record Identifier: 991031614869102976