Schlosser Kenny, Taha Mohamad, Deng Yupu, Jiang Baohua, Stewart Duncan J
From the Regenerative Medicine Program, Ottawa Hospital Research Institute), Ottawa, ON, Canada.
From the Regenerative Medicine Program, Ottawa Hospital Research Institute), Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
Chest. 2015 Aug;148(2):481-490. doi: 10.1378/chest.14-2169.
The dysregulation of microRNA (miRNA) is known to contribute to the pathobiology of pulmonary arterial hypertension (PAH). However, the relationships between changes in tissue and circulating miRNA levels associated with different animal models and human pulmonary hypertension (PH) have not been defined.
A set of miRNAs that have been causally implicated in PH, including miR-17, -21, -130b, -145, -204, -424, and -503, were measured by reverse transcription-quantitative polymerase chain reaction in the plasma, lung, and right ventricle of three of the most common rodent models of PH: the rat monocrotaline and SU5416 plus chronic hypoxia (SuHx) models and the mouse chronic hypoxia model. Plasma miRNA levels were also evaluated in a cohort of patients with PAH and healthy subjects.
Several miRNA showed PH model-dependent perturbations in plasma and tissue levels; however, none of these were conserved across all three experimental models. Principle component analysis of miR expression changes in plasma revealed distinct clustering between rodent models, and SuHx-triggered PH showed the greatest similarity to human PAH. Changes in the plasma levels of several miRNA also correlated with changes in tissue expression. In particular, miR-424 was concordantly increased (1.3- to 1.5-fold, P < .05) in the plasma, lung, and right ventricle of hypoxic mice and in the plasma of patients with PAH.
miRNAs with established etiologic roles in PH showed context-dependent changes in tissue and circulating levels, which were not consistent across rodent models and human PAH. This suggests different miRNA-dependent mechanisms may contribute to experimental and clinical PH, complicating potential diagnostic and therapeutic applications amenable to these miRNAs.
已知微小RNA（miRNA）失调与肺动脉高压（PAH）的病理生物学有关。然而，与不同动物模型和人类肺动脉高压（PH）相关的组织和循环miRNA水平变化之间的关系尚未明确。
通过逆转录定量聚合酶链反应测定了一组与PH有因果关系的miRNA，包括miR-17、-21、-130b、-145、-204、-424和-503，这些miRNA存在于三种最常见的啮齿动物PH模型的血浆、肺和右心室中，即大鼠野百合碱和SU5416加慢性缺氧（SuHx）模型以及小鼠慢性缺氧模型。还评估了一组PAH患者和健康受试者的血浆miRNA水平。
几种miRNA在血浆和组织水平上表现出与PH模型相关的扰动；然而，在所有三个实验模型中均未发现这些miRNA是保守的。对血浆中miR表达变化的主成分分析显示，啮齿动物模型之间存在明显的聚类，并且SuHx引发的PH与人类PAH表现出最大的相似性。几种miRNA的血浆水平变化也与组织表达变化相关。特别是，缺氧小鼠的血浆、肺和右心室以及PAH患者的血浆中miR-424均一致升高（1.3至1.5倍，P <.05）。
在PH中具有既定病因作用的miRNA在组织和循环水平上表现出依赖于背景的变化，这些变化在啮齿动物模型和人类PAH中并不一致。这表明不同的miRNA依赖性机制可能导致实验性和临床性PH，使适用于这些miRNA的潜在诊断和治疗应用变得复杂。
