5 -羟色胺转运体是否参与肺动脉高压的发病机制?

S. Eddahibi, B. Raffestin, M. Hamon, S. Adnot
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引用次数: 77

摘要

研究5-羟色胺(5-HT)和5-羟色胺转运体(5-HTT)对肺循环的影响是特别有趣的,因为有报道称,使用一些干扰5-HT的食欲抑制剂的患者原发性肺动脉高压(PPH)的风险增加。除了其血管活性作用外,5-HT还对肺动脉平滑肌细胞(PASMCs)产生有丝分裂和致comitogenic效应。这些促有丝分裂和致comitogenic效应需要5-HT被高亲和力的5-HTT内化,这可以被氟西汀和帕罗西汀等特定药物竞争性地抑制。在最近的一项研究中,我们发现缺氧增加了PASMCs中5-HT基因的转录率,并增强了5-HT对这些细胞的促生长作用。长期缺氧大鼠肺动脉重构平滑肌细胞中5-HTT信使核糖核酸水平升高。两组特别相关的数据进一步支持了5-HT在PASMC体内增殖中起关键作用的观点:(1)增加血浆5-HT水平的治疗会加重长期缺氧大鼠的肺动脉高压,而这种影响可以通过联合5-HTT抑制剂同时治疗来预防;(2) 5-HTT基因破坏的敲除小鼠表现出较低程度的缺氧肺动脉高压和肺血管重构,尽管缺氧肺血管收缩增加。这些观察结果表明,5-HTT在PASMCs中的表达、活性或两者都有助于肺血管重构,一些食欲抑制剂对肺动脉高压的诱导作用可能与这些药物对5-HTT表达、活性或两者的影响有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension?
Investigations on the effects of serotonin (5-HT) and the serotonin transporter (5-HTT) on the pulmonary circulation are of special interest because of the reported increased risk of primary pulmonary hypertension (PPH) in patients who used some appetite suppressants that interfere with 5-HT. In addition to its vasoactive effects, 5-HT exerts mitogenic and comitogenic effects on pulmonary artery smooth muscle cells (PASMCs). These mitogenic and comitogenic effects require 5-HT internalization by the high-affinity 5-HTT, which can be competitively inhibited by specific drugs such as fluoxetine and paroxetine. In a recent study, we showed that hypoxia increases the rate of 5-HTT gene transcription in PASMCs and potentiates the growth-promoting effect of 5-HT on these cells. An increase in the levels of 5-HTT messenger ribonucleic acid was observed in smooth-muscle cells from remodeled pulmonary arteries in rats subjected to long-term hypoxia. Two series of especially relevant data further support the idea that 5-HT plays a key role in PASMC proliferation in vivo: (1) treatments that increase plasma 5-HT levels aggravate pulmonary hypertension in rats subjected to long-term hypoxia, and this effect can be prevented by combined simultaneous treatment with 5-HTT inhibitors; and (2) knockout mice with disruption of the 5-HTT gene exhibit lesser degree of hypoxic pulmonary hypertension and pulmonary vascular remodeling than control mice despite increased hypoxic pulmonary vasoconstriction. These observations indicate that 5-HTT expression, activity, or both in PASMCs contribute to pulmonary vascular remodeling and that the inducing effects of some appetite suppressants on pulmonary hypertension may be related to possible effects of these drugs on 5-HTT expression, activity, or both.
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