Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice
Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice
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DOI：
10.1161/circulationaha.108.767558
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发表时间：
2008-06-03
期刊：
影响因子：
37.8
通讯作者：
MacLean, Margaret R.
中科院分区：
文献类型：
--
作者：
Dempsie, Yvonne;Morecroft, Ian;MacLean, Margaret R.
背景：使用间接5-羟色胺能激动剂如氨瑞克斯和右芬氟拉明引起的继发性肺动脉高压的发生率导致了肺动脉高压的“5-羟色胺假说”；然而，5-羟色胺在右芬氟拉明诱导的肺动脉高压中的作用仍然存在争议。在这里，我们使用了新的缺乏外周5-羟色胺的转基因小鼠(缺乏色氨酸羟基酶-1；TPH1(-/-)小鼠)或过表达人类5-羟色胺转运蛋白基因(SERT；SERT+小鼠)来进一步研究这一问题。Kg(-1)。D(-1PO，28天)可增加野生型小鼠右室收缩压和肺血管重构，但对TPH1(-/-)小鼠无明显影响，提示右芬氟拉明诱导的肺动脉高压依赖于5-羟色胺的合成。右芬氟拉明也用于常氧SERT+小鼠和慢性低氧SERT+小鼠。右芬氟拉明和SERT过表达在增加肺血管重构方面具有相加作用；然而，在低氧SERT+小鼠中，右芬氟拉明降低了右心室收缩压和肺血管重构。SERT+小鼠的肺动脉成纤维细胞在低氧条件下增殖，而野生型小鼠则不然。右芬氟拉明以SERT活性依赖的方式抑制低氧诱导的SERT+小鼠肺动脉成纤维细胞的增殖。结论：外周5-羟色胺在右芬氟拉明诱导的肺动脉高压的发生发展中起重要作用，右芬氟拉明和SERT的过度表达在肺血管重构中具有相加作用。我们认为右芬氟拉明也可以通过SERT活性和抑制低氧诱导的p38丝裂原活化蛋白激酶来抑制低氧诱导的肺血管重构。
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.