Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease.
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 S100beta, 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.
Department of Pediatrics, Stanford University School of Medicine, CCSR Rm 2245B, 269 Campus Dr, Stanford, CA 93405-5162, USA.
Allan
A
Lawrie
Edda
E
Spiekerkoetter
Eliana C
EC
Martinez
Noona
N
Ambartsumian
W John
WJ
Sheward
Margaret R
MR
MacLean
Anthony J
AJ
Harmar
Ann-Marie
AM
Schmidt
Eugene
E
Lukanidin
Marlene
M
Rabinovitch
D021581:Active Transport, Cell Nucleus; D002465:Cell Movement; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D050991:GATA4 Transcription Factor; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008995:Monoamine Oxidase / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000166:cytology; D044302:Receptor, Serotonin, 5-HT1B / Q000502:physiology*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D017127:Glycation End Products, Advanced; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D044302:Receptor, Serotonin, 5-HT1B; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D014157:Transcription Factors; C077591:S100A4 protein, human; D012701:Serotonin; D008995:Monoamine Oxidase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3