期刊
CIRCULATION
卷 117, 期 22, 页码 2928-2937出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.108.767558
关键词
hypertension, pulmonary; hypoxia; dexfenfluramine; serotonin
资金
- Biotechnology and Biological Sciences Research Council Funding Source: Medline
- British Heart Foundation Funding Source: Medline
- Medical Research Council Funding Source: Medline
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.
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