Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension
Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension
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DOI：
10.1038/nm764
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发表时间：
2002-10-01
期刊：
影响因子：
82.9
通讯作者：
Maroteaux, L
中科院分区：
文献类型：
--
作者：
Launay, JM;Hervé, P;Maroteaux, L
原发性肺动脉高压是一种进行性疾病，通常是致命的，它是由与异常血管增生相关的肺动脉血压升高引起的。右芬氟拉明增加人类肺动脉高压的风险，其活性代谢物是选择性5-羟色胺2B（5-HT 2B）受体激动剂。因此，我们研究了5-HT 2B受体在肺动脉高压发病机制中的作用。使用慢性低氧小鼠肺动脉高压模型，我们发现肺动脉血压和肺重塑的低氧依赖性增加与血管增殖，弹性蛋白酶活性和转化生长因子-β水平的增加有关，并且这些参数通过右芬氟拉明治疗增强。与此相反，缺氧小鼠与遗传或代谢失活的5-HT 2B受体表现出任何这些参数没有变化。在人类和小鼠中，肺动脉高压与肺动脉中5-HT 2B受体表达的显著增加相关。这些数据表明，5-HT 2B受体的激活是肺动脉高压发展的限制性步骤。
Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT2B) receptor agonist. Thus, we investigated the contribution of the 5-HT2B receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT2B receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT2B receptor expression in pulmonary arteries. These data show that activation of 5-HT2B receptors is a limiting step in the development of pulmonary hypertension.