Gibb Andrew A, LaPenna Kyle, Gaspar Ryan B, Latchman Nadina R, Tan Yinfei, Choya-Foces Carmen, Doiron Jake E, Li Zhen, Xia Huijing, Lazaropoulos Michael P, Conwell Mariell, Sharp Thomas E, Goodchild Traci T, Lefer David J, Elrod John W
Center for Cardiometabolic Science, Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville, Louisville, KY, USA.
Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
bioRxiv. 2024 Oct 25:2024.10.25.619450. doi: 10.1101/2024.10.25.619450.
Heart failure with preserved ejection fraction (HFpEF) accounts for ~50% of HF cases, with no effective treatments. The ZSF1-obese rat model recapitulates numerous clinical features of HFpEF including hypertension, obesity, metabolic syndrome, exercise intolerance, and LV diastolic dysfunction. Here, we utilized a systems-biology approach to define the early metabolic and transcriptional signatures to gain mechanistic insight into the pathways contributing to HFpEF development.
Male ZSF1-obese, ZSF1-lean hypertensive controls, and WKY (wild-type) controls were compared at 14w of age for extensive physiological phenotyping and LV tissue harvesting for unbiased metabolomics, RNA-sequencing, and assessment of mitochondrial morphology and function. Utilizing ZSF1-lean and WKY controls enabled a distinction between hypertension-driven molecular changes contributing to HFpEF pathology, versus hypertension + metabolic syndrome.
ZSF1-obese rats displayed numerous clinical features of HFpEF. Comparison of ZSF1-lean vs WKY (i.e., hypertension-exclusive effects) revealed metabolic remodeling suggestive of increased aerobic glycolysis, decreased β-oxidation, and dysregulated purine and pyrimidine metabolism with few transcriptional changes. ZSF1-obese rats displayed worsened metabolic remodeling and robust transcriptional remodeling highlighted by the upregulation of inflammatory genes and downregulation of the mitochondrial structure/function and cellular metabolic processes. Integrated network analysis of metabolomic and RNAseq datasets revealed downregulation of nearly all catabolic pathways contributing to energy production, manifesting in a marked decrease in the energetic state (i.e., reduced ATP/ADP, PCr/ATP). Cardiomyocyte ultrastructure analysis revealed decreased mitochondrial area, size, and cristae density, as well as increased lipid droplet content in HFpEF hearts. Mitochondrial function was also impaired as demonstrated by decreased substrate-mediated respiration and dysregulated calcium handling.
Collectively, the integrated omics approach applied here provides a framework to uncover novel genes, metabolites, and pathways underlying HFpEF, with an emphasis on mitochondrial energy metabolism as a potential target for intervention.
射血分数保留的心力衰竭（HFpEF）约占心力衰竭病例的50%，且尚无有效治疗方法。ZSF1肥胖大鼠模型再现了HFpEF的众多临床特征，包括高血压、肥胖、代谢综合征、运动不耐受和左心室舒张功能障碍。在此，我们采用系统生物学方法来定义早期代谢和转录特征，以深入了解导致HFpEF发生发展的机制。
在14周龄时，对雄性ZSF1肥胖大鼠、ZSF1瘦型高血压对照大鼠和WKY（野生型）对照大鼠进行广泛的生理表型分析，并采集左心室组织用于无偏向代谢组学、RNA测序以及线粒体形态和功能评估。利用ZSF1瘦型大鼠和WKY对照大鼠能够区分导致HFpEF病理的高血压驱动的分子变化与高血压+代谢综合征。
ZSF1肥胖大鼠表现出HFpEF的众多临床特征。ZSF1瘦型大鼠与WKY大鼠的比较（即仅高血压的影响）显示代谢重塑，提示有氧糖酵解增加、β-氧化减少以及嘌呤和嘧啶代谢失调，转录变化较少。ZSF1肥胖大鼠表现出更严重的代谢重塑和强烈的转录重塑，其特征为炎症基因上调以及线粒体结构/功能和细胞代谢过程下调。代谢组学和RNA测序数据集的综合网络分析显示，几乎所有有助于能量产生的分解代谢途径均下调，表现为能量状态显著降低（即ATP/ADP、PCr/ATP降低）。心肌细胞超微结构分析显示，HFpEF心脏中的线粒体面积、大小和嵴密度降低，脂滴含量增加。线粒体功能也受损，表现为底物介导的呼吸减少和钙处理失调。
总体而言，本文应用的综合组学方法提供了一个框架，以揭示HFpEF潜在的新基因、代谢物和途径，重点是将线粒体能量代谢作为潜在的干预靶点。
