Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension
Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension
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DOI：
10.1152/ajplung.00453.2016
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发表时间：
2017-08-01
影响因子：
4.9
通讯作者：
Perez, Vinicio A. de Jesus
中科院分区：
文献类型：
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作者：
Orcholski, Mark E.;Khurshudyan, Artyom;Perez, Vinicio A. de Jesus
肺动脉高压是甲基苯丙胺（METH-PAH）使用的并发症，但其发病机制尚不清楚。鉴于细胞色素 P450 2D6 (CYP2D6) 和羧酸酯酶 1 (CES1) 参与 METH 和其他苯丙胺类化合物的代谢，我们推测功能变异的丧失可能导致 METH-PAH。尽管肺免疫荧光未发现 CYP2D6 表达存在差异，但 METH-PAH 微血管内皮细胞中 CES1 表达显着降低。质谱分析表明，健康的肺微血管内皮细胞（PMVEC）具有内化和代谢冰毒的能力。此外，18 名 METH-PAH 患者的全外显子组测序数据显示，94.4% 的 METH-PAH 患者是单核苷酸变异（SNV；rs115629050）的杂合携带者，预计会降低 CES1 活性。转染这种 CES1 变体的 PMVEC 表现出明显更高的 METH 诱导的细胞凋亡率。接触冰毒会导致活性氧 (ROS) 的形成增加和补偿性自噬反应。与健康细胞相比，CES1 缺陷的 PMVEC 尽管具有较高的 ROS（与细胞凋亡增加相关），但缺乏强大的自噬反应。我们认为，CES1 表达/活性降低可以通过增加 PMVEC 凋亡和小血管损失来促进 METH-PAH 的发展。
Pulmonary arterial hypertension is a complication of methamphetamine use (METH-PAH), but the pathogenic mechanisms are unknown. Given that cytochrome P450 2D6 (CYP2D6) and carboxylesterase 1 (CES1) are involved in metabolism of METH and other amphetamine-like compounds, we postulated that loss of function variants could contribute to METH-PAH. Although no difference in CYP2D6 expression was seen by lung immunofluorescence, CES1 expression was significantly reduced in endothelium of METH-PAH microvessels. Mass spectrometry analysis showed that healthy pulmonary microvascular endothelial cells (PMVECs) have the capacity to both internalize and metabolize METH. Furthermore, whole exome sequencing data from 18 METH-PAH patients revealed that 94.4% of METH-PAH patients were heterozygous carriers of a single nucleotide variant (SNV; rs115629050) predicted to reduce CES1 activity. PMVECs transfected with this CES1 variant demonstrated significantly higher rates of METH-induced apoptosis. METH exposure results in increased formation of reactive oxygen species (ROS) and a compensatory autophagy response. Compared with healthy cells, CES1-deficient PMVECs lack a robust autophagy response despite higher ROS, which correlates with increased apoptosis. We propose that reduced CES1 expression/activity could promote development of METH-PAH by increasing PMVEC apoptosis and small vessel loss.