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

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Item Type:	Article
Title:	Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice
Creators Name:	Dempsie, Y., Morecroft, I., Welsh, D.J., Macritchie, N.A., Herold, N., Loughlin, L., Nilsen, M., Peacock, A.J., Harmar, A., Bader, M. and Maclean, M.R.
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. Methods and Results-Dexfenfluramine administration (5 mg . kg(-1) . 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.
Keywords:	Hypertension, Pulmonary, Hypoxia, Dexfenfluramine, Serotonin, Animals, Mice
Source:	Circulation
ISSN:	0009-7322
Publisher:	American Heart Association
Volume:	2008
Number:	117
Page Range:	2928-2937
Date:	3 June 2008
Official Publication:	https://doi.org/10.1161/CIRCULATIONAHA.108.767558
PubMed:	View item in PubMed

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