A Multi-omic and Multi-Species Analysis of Right Ventricular Failure

Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no approved RV-targeted treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. Here, we used transcriptomics and proteomics analyses to define the molecular pathways associated with cardiac MRI-derived values of RV hypertrophy, dilation, and dysfunction in pulmonary artery banded (PAB) piglets. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare the three species. Transcriptomic and proteomic analyses identified changes in multiple metabolic pathways in the RV of PAB pigs, and pathway alterations that were conserved between species. However, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across species. FAO and ETC proteins and transcripts were mostly downregulated in rats, but were predominately upregulated in PAB pigs. When compared to humans, the pig PAB molecular signature was more similar to patients with RVF than rodents. These data suggest there are divergent molecular responses of RVF across species, and pigs more accurately recapitulate the metabolic molecular signature of human RVF. Overall design: RNA from bulk RV free wall tissue from control pigs and pulmonary artery banded pigs

右心衰竭（Right ventricular failure, RVF）是多种心血管疾病首要的发病与死亡诱因之一，但目前尚无获批的右心靶向治疗药物，因其治疗靶点尚未明确。当前针对RVF的转录组学/蛋白质组学研究多集中于小型动物实验，大型动物模型相关数据仍较为匮乏。此外，目前仍缺乏跨物种RVF分子介导因子的对比分析。本研究通过转录组学与蛋白质组学分析，明确了肺动脉环扎（pulmonary artery banded, PAB）幼猪右心室中，与心脏磁共振成像测得的右心室肥厚、扩张及功能异常相关的分子通路。随后，我们利用公开的大鼠野百合碱诱导RVF模型数据，以及右心室功能保留或受损的肺动脉高压患者的公开数据，对三个物种的相关数据开展对比分析。转录组与蛋白质组分析显示，PAB猪的右心室存在多条代谢通路的异常改变，且存在跨物种保守的通路调控异常。不过，不同物种间脂肪酸氧化（fatty acid oxidation, FAO）与电子传递链（electron transport chain, ETC）蛋白的紊乱模式存在差异：大鼠的FAO与ETC相关蛋白及转录本大多呈现下调趋势，而PAB猪则以上调为主要特征。与人类数据相比，PAB猪的分子特征与RVF患者更为相似，而非啮齿类动物。上述数据表明，不同物种的RVF分子应答存在分化，而猪模型能更准确地复现人类RVF的代谢分子特征。整体实验设计：采集对照组与肺动脉环扎猪的大块右心室游离壁组织的总RNA