The serotonin hypothesis of pulmonary hypertension revisited.
The serotonin hypothesis of pulmonary arterial hypertension (PAH) arose after an outbreak of PAH in patients taking the anorexigenic drugs aminorex and dexfenfluramine. Both of these drugs are serotonin transporter (SERT) substrates and indirect serotinergic agonists. There is now a wealth of evidence to support a role for serotonin in the pathobiology of PAH. Synthesis of serotonin can occur in pulmonary artery endothelial cells by the enzyme tryptophan hydroxylase 1 (TPH1). Serotonin then acts at the 5-HT(1B) receptor and the SERT to mediate constriction and proliferation of pulmonary artery smooth muscle cells. Downstream signalling molecules which play a role in serotonin-induced constriction and proliferation include reactive oxygen species (ROS), Rho-kinase (ROCK) p38 and extracellular signal-regulated kinase (ERK). There is also evidence to suggest that serotonin may interact with the bone morphogenetic receptor type II (BMPRII) to provide a 'second hit' risk factor for PAH.
Maclean
Margaret R
MR
Integrative and Systems Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, Scotland, UK. m.maclean@bio.gla.ac.uk
Dempsie
Yvonne
Y
D000818:Animals; D001067:Appetite Depressants / Q000009:adverse effects / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D020372:Dexfenfluramine / Q000009:adverse effects / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology
D001067:Appetite Depressants; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D020372:Dexfenfluramine; D052006:Bone Morphogenetic Protein Receptors, Type II