Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice

Circulation. 2008 Jun 3;117(22):2928-37. doi: 10.1161/CIRCULATIONAHA.108.767558. Epub 2008 May 27.


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.

Methods and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dexfenfluramine / adverse effects*
  • Hypertension, Pulmonary / chemically induced*
  • Hypoxia
  • Mice
  • Mice, Transgenic
  • Serotonin / physiology*
  • Serotonin Plasma Membrane Transport Proteins / physiology
  • Serotonin Receptor Agonists / adverse effects
  • Tryptophan Hydroxylase / deficiency
  • Tryptophan Hydroxylase / physiology
  • p38 Mitogen-Activated Protein Kinases


  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Receptor Agonists
  • Serotonin
  • Dexfenfluramine
  • Tryptophan Hydroxylase
  • p38 Mitogen-Activated Protein Kinases