Heart failure (HF) patients with deteriorating right ventricular (RV) structure and function have a nearly two-fold increased risk of death compared to those without. Despite the well-established clinical risk, few studies have examined the molecular signature associated with this HF condition. The purpose of this study was to integrate morphological, molecular, and functional data with the transcriptome dataset in the RV of a pre-clinical model of cardio-metabolic HF. Ossabaw swine were fed either normal diet without surgery (lean control, n=5) or Western Diet and aortic-banding (WD-AB; n=4). Postmortem RV weight was increased and positively correlated with lung weight in the WD-AB group compared to CON. Total RNA-seq was performed and gene expression profiles were compared and analyzed using Principal Component Analysis, Weighted Gene Co-Expression Network Analysis, Module Enrichment Analysis, and Ingenuity Pathway Analysis. Gene networks specifically associated with RV hypertrophic remodeling identified a hub gene in MAPK8 (or JNK1) that was associated with the selective induction of the extracellular matrix (ECM) component fibronectin. JNK1 and fibronectin protein were increased in the right coronary artery (RCA) of WD-AB animals and associated with a decrease in matrix metalloproteinase 14 protein, which specifically degrades fibronectin. RCA fibronectin content was correlated with increased vascular stiffness evident as a decreased elastin elastic modulus in WD-AB animals. In conclusion, this study establishes a molecular and transcriptome signature in the RV using Ossabaw swine with cardio-metabolic HF. This signature was associated with altered ECM regulation and increased vascular stiffness in the RCA, with selective dysregulation of fibronectin.

中文翻译：

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患有心脏代谢性心力衰竭的奥萨博猪的右心室转录组特征：对冠状动脉血管系统的影响

右心室（RV）结构和功能恶化的心力衰竭（HF）患者的死亡风险比没有恶化的患者增加近两倍。尽管存在明确的临床风险，但很少有研究检查与这种心力衰竭病症相关的分子特征。本研究的目的是将形态学、分子和功能数据与心脏代谢性心力衰竭临床前模型 RV 中的转录组数据集进行整合。奥萨博猪要么喂食正常饮食，无需手术（瘦肉对照，n = 5），要么喂食西方饮食和主动脉束带术（WD-AB；n = 4）。与 CON 相比，WD-AB 组死后 RV 重量增加，且与肺重量呈正相关。进行总 RNA 测序，并使用主成分分析比较和分析基因表达谱，加权基因共表达网络分析、模块富集分析和独创性路径分析。与 RV 肥大重塑特别相关的基因网络在 MAPK8（或 JNK1）中发现了一个与细胞外基质（ECM）成分纤连蛋白的选择性诱导相关的中心基因。WD-AB 动物的右冠状动脉 (RCA) 中 JNK1 和纤连蛋白增加，并与特异性降解纤连蛋白的基质金属蛋白酶 14 蛋白减少相关。RCA 纤连蛋白含量与血管硬度增加相关，这在 WD-AB 动物中表现为弹性蛋白弹性模量的降低。总之，本研究使用患有心脏代谢性心力衰竭的 Ossabaw 猪，在 RV 中建立了分子和转录组特征。