Hypoxia-induced changes in plasma micro-RNAs correlate with pulmonary artery pressure at high altitude
Hypoxia-induced changes in plasma micro-RNAs correlate with pulmonary artery pressure at high altitude
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DOI：
10.1152/ajplung.00146.2017
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发表时间：
2018-01-01
影响因子：
4.9
通讯作者：
Hefti, Jacqueline Pichler
中科院分区：
文献类型：
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作者：
Blissenbach, Birgit;Nakas, Christos T.;Hefti, Jacqueline Pichler
体外和动物研究表明 micro-RNA (miR) 参与调节缺氧诱导的肺动脉高压 (HPH)。然而，对于 HPH 背景下人类循环 miR 的了解非常有限。由于 HPH 的症状是非特异性的，并且不存在非侵入性诊断参数，因此指示 HPH 的疾病特异性且与低氧血症无关的生物标志物将具有临床价值。为了检查血浆 miR 水平是否与缺氧引起的肺动脉压力升高相关，在暴露于极端海拔的人类缺氧相关肺动脉高压模型中评估了血浆 miR。 40名健康志愿者在海拔7,050 m的高海拔探险中接受了重复检查。通过实时定量 PCR 测量 miR-17、-21 和 -190 的血浆水平，并与通过超声心动图评估的肺动脉收缩压 (SPAP) 相关。发现循环 miR 表达存在显着的海拔依赖性增加（所有 P 值 < 0.0001）。与500 m处的基线相比，在7,050 m处，miR-17变化了4.72 +/- 0.57倍，miR-21变化了1.91 +/- 0.33倍，miR-190变化了3.61 +/- 0.54倍（平均值+/- SD）。即使在调整低氧血症后，仍发现 miR-17 和 miR-190 与 SPAP 增加独立相关。进行性低压缺氧显着影响循环 miR-17、-21 和 -190 的水平。独立于低氧血症的程度，miR-17和-190与SPAP增加显着相关。这些新发现为 miR-17 和 -190 对缺氧诱导的肺动脉压力增加进行表观遗传调节提供了证据，并表明这些 miR 作为 HPH 生物标志物的潜在价值。
In vitro and animal studies revealed micro-RNAs (miRs) to be involved in modulation of hypoxia-induced pulmonary hypertension (HPH). However, knowledge of circulating miRs in humans in the context of HPH is very limited. Since symptoms of HPH are nonspecific and noninvasive diagnostic parameters do not exist, a disease-specific and hypoxemia-independent biomarker indicating HPH would be of clinical value. To examine whether plasma miR levels correlate with hypoxia-induced increase in pulmonary artery pressures, plasma miRs were assessed in a model of hypoxia-related pulmonary hypertension in humans exposed to extreme altitude. Forty healthy volunteers were repetitively examined during a high-altitude expedition up to an altitude of 7,050 m. Plasma levels of miR-17, -21, and -190 were measured by real-time quantitative PCR and correlated with systolic pulmonary artery pressure (SPAP), which was assessed by echocardiography. A significant altitude-dependent increase in circulating miR expression was found (all P values < 0.0001). Compared with baseline at 500 m, miR-17 changed by 4.72 +/- 0.57-fold, miR-21 changed by 1.91 +/- 0.33-fold, and miR-190 changed by 3.61 +/- 0.54-fold at 7,050 m (means +/- SD). Even after adjusting for hypoxemia, miR-17 and miR-190 were found to be independently correlated with increased SPAP. Progressive hypobaric hypoxia significantly affects levels of circulating miR-17, -21, and -190. Independently from the extent of hypoxemia, miR-17 and -190 significantly correlate with increased SPAP. These novel findings provide evidence for an epigenetic modulation of hypoxia-induced increase in pulmonary artery pressures by miR-17 and -190 and suggest the potential value of these miRs as biomarkers for HPH.