Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension
Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension
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DOI：
10.1172/jci200112805
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发表时间：
2001-10-01
影响因子：
15.9
通讯作者：
Adnot, S
中科院分区：
文献类型：
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作者：
Eddahibi, S;Humbert, M;Adnot, S
肺动脉平滑肌细胞（PA-SMCs）增生是原发性肺动脉高压（PPH）的标志性病理特征。在这里，我们发现，PA-SMCs从PPH患者的生长速度比PA-SMCs从对照组时，血清素或血清刺激，这些影响是由于5-羟色胺转运蛋白（5-HTT），介导的吲哚胺的内化表达增加。在5-HTT抑制剂的存在下，血清和5-羟色胺的生长刺激作用显着降低，不再观察到患者和对照组的PA-SMCs生长之间的差异。与对照组相比，5-HTT的表达在培养的PA-SMCs以及PPH患者的血小板和肺中增加，其中5-HTT在增厚的肺动脉中膜和洋葱球病变中占主导地位。5 HTT基因启动子的L-等位基因变体与5-HTT过表达和PA-SMC生长增加相关，在65%的患者中以纯合形式存在，但仅在27%的对照中存在。我们的结论是，5-HTT活性在PPH的PA-SMC增殖的发病机制中起着关键作用，5 HTT多态性赋予PPH的易感性。
Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of primary pulmonary hypertension (PPH). Here we found that PA-SMCs from patients with PPH grow faster than PA-SMCs from controls when stimulated by serotonin or serum and that these effects are due to increased expression of the serotonin transporter (5-HTT), which mediates internalization of indoleamine. In the presence of 5-HTT inhibitors, the growth stimulatory effects of serum and serotonin were markedly reduced and the difference between growth of PA-SMCs from patients and controls was no longer observed. As compared with controls, the expression of 5-HTT was increased in cultured PA-SMCs as well as in platelets and lungs from patients with PPH where it predominated in the media of thickened pulmonary arteries and in onion-bulb lesions. The L-allelic variant of the 5HTT gene promoter, which is associated with 5-HTT overexpression and increased PA-SMC growth, was present in homozygous form in 65% of patients but in only 27% of controls. We conclude that 5-HTT activity plays a key role in the pathogenesis of PA-SMC proliferation in PPH and that a 5HTT polymorphism confers susceptibility to PPH.