Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice
Y Dempsie, I Morecroft, DJ Welsh, NA MacRitchie… - Circulation, 2008 - Am Heart Assoc
Y Dempsie, I Morecroft, DJ Welsh, NA MacRitchie, N Herold, L Loughlin, M Nilsen…
Circulation, 2008•Am Heart AssocBackground—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; …
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; …
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.
Am Heart Assoc