Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany.
Department of Physiology, Justus Liebig University, Giessen, Germany.
Nat Cardiovasc Res. 2024 Jul;3(7):819-840. doi: 10.1038/s44161-024-00485-1. Epub 2024 Jul 5.
The molecular mechanisms of progressive right heart failure are incompletely understood. In this study, we systematically examined transcriptomic changes occurring over months in isolated cardiomyocytes or whole heart tissues from failing right and left ventricles in rat models of pulmonary artery banding (PAB) or aortic banding (AOB). Detailed bioinformatics analyses resulted in the identification of gene signature, protein and transcription factor networks specific to ventricles and compensated or decompensated disease states. Proteomic and RNA-FISH analyses confirmed PAB-mediated regulation of key genes and revealed spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with transcriptome datasets from human patients with chronic thromboembolic pulmonary hypertension (CTEPH) led to the identification of more than 50 genes whose expression levels correlated with the severity of right heart disease, including multiple matrix-regulating and secreted factors. These data define a conserved, differentially regulated genetic network associated with right heart failure in rats and humans.
右心衰竭的分子机制尚不完全清楚。在这项研究中，我们系统地检测了肺动脉缩窄（PAB）或主动脉缩窄（AOB）大鼠模型中分离的心肌细胞或衰竭右心室和左心室的心脏组织中数月来发生的转录组变化。详细的生物信息学分析确定了特定于心室和代偿或失代偿疾病状态的基因特征、蛋白质和转录因子网络。蛋白质组学和 RNA-FISH 分析证实了 PAB 对关键基因的调节，并揭示了心脏中空间异质性的 mRNA 表达。大鼠 PAB 特异性基因集与慢性血栓栓塞性肺动脉高压（CTEPH）患者的转录组数据集的交集导致鉴定出 50 多个基因，其表达水平与右心疾病的严重程度相关，包括多个基质调节和分泌因子。这些数据定义了一个与大鼠和人类右心衰竭相关的保守的、差异调节的遗传网络。
