Transcriptomic Analysis of Right Ventricular Remodeling in Two Rat Models of Pulmonary Hypertension: Identification and Validation of Epithelial-to-Mesenchymal Transition in Human Right Ventricular Failure.
Transcriptomic Analysis of Right Ventricular Remodeling in Two Rat Models of Pulmonary Hypertension: Identification and Validation of Epithelial-to-Mesenchymal Transition in Human Right Ventricular Failure.
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两种大鼠肺动脉高压模型中右室重构的转录转录分析：人右室衰竭中上皮向间充质转变的识别和验证。
DOI：
10.1161/circheartfailure.120.007058
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Umar S
中科院分区：
文献类型：
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作者：
Park JF;Clark VR;Banerjee S;Hong J;Razee A;Williams T;Fishbein G;Saddic L;Umar S
右心室（RV）功能障碍是肺动脉高压（PAH）发病率和死亡率的重要预后决定因素。尽管 RV 功能在 PAH 中很重要，但继发于 PAH 的 RV 功能障碍的潜在分子机制仍不清楚。我们的目标是利用两种临床相关 PAH 动物模型的 RV 组织的 RNA 测序来识别和比较 RV 衰竭的分子决定因素。我们对接受野百合碱 (MCT) 或 Sugen 缺氧/常氧 (SuHx) 治疗的大鼠的 RV 进行了 RNA 测序。通过导管插入术和超声心动图证实 PAH 和 RV 衰竭。我们使用定量实时 PCR、免疫荧光和蛋白质印迹验证了 RV 转录组结果。对对照 (n=3) 和 PAH 诱导的 RV 衰竭患者 (n=5) 的人类 RV 组织进行免疫组织化学和免疫荧光检查。我们从 MCT 和 SuHx 诱导的 RV 衰竭中鉴定出相似的 RV 转录组谱。通路分析显示，上皮间质转化 (EMT)、炎症和代谢方面的基因丰富。对继发于 PAH 的 RV 衰竭患者的人类 RV 组织进行组织学染色显示，与正常 RV 相比，血管周围区域存在显着的 RV 纤维化和内皮间质转化 (EndMT)，以及 CCN2（涉及 EMT/EndMT 的顶级基因）表达升高。 MCT 和 SuHx 模型中 RV 衰竭的转录组学特征显示出相似的基因表达和生物学途径。我们使用 PAH 患者的 RV 提供了该转录组特征的翻译相关性，以证明 EMT/EndMT 和 CCN2 (CTGF) 蛋白表达的证据。针对 MCT 和 SuHx 模型中导致 RV 衰竭的特定分子机制，可能会确定 PAH 相关 RV 衰竭的新治疗策略。
Right ventricular (RV) dysfunction is a significant prognostic determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Despite the importance of RV function in PAH, the underlying molecular mechanisms of RV dysfunction secondary to PAH remain unclear. We aim to identify and compare molecular determinants of RV failure using RNA-sequencing of RV tissue from two clinically relevant animal models of PAH. We performed RNA-sequencing on RV from rats treated with monocrotaline (MCT) or Sugen with hypoxia/normoxia (SuHx). PAH and RV failure were confirmed by catheterization and echocardiography. We validated the RV transcriptome results using quantitative real-time PCR, immunofluorescence and Western blot. Immunohistochemistry and immunofluorescence were performed on human RV tissue from control (n=3) and PAH-induced RV failure patients (n=5). We identified similar transcriptomic profiles of RV from MCT- and SuHx-induced RV-failure. Pathway analysis showed genes enriched in epithelial-to-mesenchymal transition (EMT), inflammation, and metabolism. Histological staining of human RV tissue from patients with RV-failure secondary to PAH revealed significant RV fibrosis and endothelial-to-mesenchymal transition (EndMT), as well as elevated CCN2 (top gene implicated in EMT/EndMT) expression in perivascular areas compared to normal RV. Transcriptomic signature of RV failure in MCT and SuHx models showed similar gene expressions and biological pathways. We provide translational relevance of this transcriptomic signature using RV from PAH patients to demonstrate evidence of EMT/EndMT and protein expression of CCN2 (CTGF). Targeting specific molecular mechanisms responsible for RV failure in MCT and SuHx models may identify novel therapeutic strategies for PAH-associated RV failure.