title: Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice.
abstract: BACKGROUND
  The incidence of pulmonary arterial hypertension secondary to the use of indirect serotinergic agonists such as aminorex and dexfenfluramine led to the "serotonin hypothesis" of pulmonary arterial hypertension; however, the role of serotonin in dexfenfluramine-induced pulmonary arterial hypertension remains controversial. Here, we used novel transgenic mice lacking peripheral serotonin (deficient in tryptophan hydroxylase-1; Tph1(-/-) mice) or overexpressing the gene for the human serotonin transporter (SERT; SERT(+) mice) to investigate this further.
  
  
  RESULTS
  Dexfenfluramine administration (5 mg x kg(-1) x d(-1) PO for 28 days) increased systolic right ventricular pressure and pulmonary vascular remodeling in wild-type mice but not in Tph1(-/-) mice, which suggests that dexfenfluramine-induced pulmonary arterial hypertension is dependent on serotonin synthesis. Dexfenfluramine was also administered to normoxic SERT(+) mice and SERT(+) mice exposed to chronic hypoxia. Dexfenfluramine and SERT overexpression had additive effects in increasing pulmonary vascular remodeling; however, in hypoxic SERT(+) mice, dexfenfluramine reduced both systolic right ventricular pressure and pulmonary vascular remodeling. Pulmonary arterial fibroblasts from SERT(+) mice, but not wild-type mice, proliferated in response to hypoxia. Dexfenfluramine inhibited hypoxia-induced proliferation of pulmonary arterial fibroblasts derived from SERT(+) mice in a manner dependent on SERT activity. Dexfenfluramine also inhibited the hypoxia-mediated increase in phosphorylation of p38 mitogen-activated protein kinase in SERT(+) pulmonary arterial fibroblasts.
  
  
  CONCLUSIONS
  The results suggest that peripheral serotonin is critical for the development of dexfenfluramine-induced pulmonary arterial hypertension and that dexfenfluramine and SERT overexpression have additive effects on pulmonary vascular remodeling. We propose that dexfenfluramine can also inhibit hypoxia-induced pulmonary vascular remodeling via SERT activity and inhibition of hypoxia-induced p38 mitogen-activated protein kinase.
authors.affiliation: Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dempsie
authors.forename: Ian
authors.initials: I
authors.lastname: Morecroft
authors.forename: David J
authors.initials: DJ
authors.lastname: Welsh
authors.forename: Neil A
authors.initials: NA
authors.lastname: MacRitchie
authors.forename: Nigel
authors.initials: N
authors.lastname: Herold
authors.forename: Lynn
authors.initials: L
authors.lastname: Loughlin
authors.forename: Margaret
authors.initials: M
authors.lastname: Nilsen
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peacock
authors.forename: Anthony
authors.initials: A
authors.lastname: Harmar
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacLean
mesh_terms: D000818:Animals; D020372:Dexfenfluramine / Q000009:adverse effects*; D006976:Hypertension, Pulmonary / Q000139:chemically induced*; D000860:Hypoxia; D051379:Mice; D008822:Mice, Transgenic; D012701:Serotonin / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000009:adverse effects; D014365:Tryptophan Hydroxylase / Q000172:deficiency / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D020372:Dexfenfluramine; D014365:Tryptophan Hydroxylase; D048051:p38 Mitogen-Activated Protein Kinases