PDF(Pubmed)
Abstract：
Aim: Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy that results in death from right ventricular failure (RVF). There is limited understanding of the molecular mechanisms of RVF in PAH. Methods: In a PAH-RVF model induced by injection of adult male rats with monocrotaline (MCT; 60 mg/kg), we performed mass spectrometry to identify proteins that change in the RV as a consequence of PAH induced RVF. Bioinformatic analysis was used to integrate our previously published RNA sequencing data from an independent cohort of PAH rats. Results: We identified 1,277 differentially regulated proteins in the RV of MCT rats compared to controls. Integration of MCT RV transcriptome and proteome data sets identified 410 targets that are concordantly regulated at the mRNA and protein levels. Functional analysis of these data revealed enriched functions, including mitochondrial metabolism, cellular respiration, and purine metabolism. We also prioritized 15 highly enriched protein:transcript pairs and confirmed their biological plausibility as contributors to RVF. We demonstrated an overlap of these differentially expressed pairs with data published by independent investigators using multiple PAH models, including the male SU5416-hypoxia model and several male rat strains. Conclusion: Multiomic integration provides a novel view of the molecular phenotype of RVF in PAH which includes dysregulation of pathways involving purine metabolism, mitochondrial function, inflammation, and fibrosis.
摘要：
目的：肺动脉高压（PAH）是一种阻塞性肺血管病变，可导致右心室衰竭（RVF）死亡。对RVF在PAH中的分子机制的理解有限。方法：在成年雄性大鼠注射野百合碱（MCT;60mg/kg）诱导的PAH-RVF模型中，我们进行了质谱分析以鉴定由于PAH诱导的RVF而导致RV变化的蛋白质。生物信息学分析用于整合我们先前发表的来自独立的PAH大鼠队列的RNA测序数据。结果：与对照组相比，我们在MCT大鼠的RV中鉴定了1,277种差异调节蛋白。MCTRV转录组和蛋白质组数据集的整合鉴定了410个在mRNA和蛋白质水平上被一致调节的靶标。对这些数据的功能分析揭示了丰富的功能，包括线粒体代谢，细胞呼吸，嘌呤代谢.我们还优先考虑了15种高度富集的蛋白质：转录物对，并确认了它们作为RVF的贡献者的生物学合理性。我们证明了这些差异表达对与独立研究人员使用多个PAH模型发布的数据的重叠，包括雄性SU5416缺氧模型和几种雄性大鼠品系。结论：多体整合提供了PAH中RVF分子表型的新观点，其中包括涉及嘌呤代谢的通路失调，线粒体功能，炎症,和纤维化。
