Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice.
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.
Dempsie
Yvonne
Y
Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Morecroft
Ian
I
Welsh
David J
DJ
MacRitchie
Neil A
NA
Herold
Nigel
N
Loughlin
Lynn
L
Nilsen
Margaret
M
Peacock
Andrew J
AJ
Harmar
Anthony
A
Bader
Michael
M
MacLean
Margaret R
MR
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
D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D020372:Dexfenfluramine; D014365:Tryptophan Hydroxylase; D048051:p38 Mitogen-Activated Protein Kinases