Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing 100871, China.
Hemorheology Center, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Int J Mol Sci. 2020 May 9;21(9):3362. doi: 10.3390/ijms21093362.
(1) Background: There are no successive treatments for heart failure with preserved ejection fraction (HFpEF) because of complex interactions between environmental, histological, and genetic risk factors. The objective of the study is to investigate changes in cardiomyocytes and molecular networks associated with HFpEF. (2) Methods: Dahl salt-sensitive (DSS) rats developed HFpEF when fed with a high-salt (HS) diet for 7 weeks, which was confirmed by in vivo and ex vivo measurements. Shotgun proteomics, microarray, Western blot, and quantitative RT-PCR analyses were further carried out to investigate cellular and molecular mechanisms. (3) Results: Rats with HFpEF showed diastolic dysfunction, impaired systolic function, and prolonged repolarization of myocytes, owing to an increase in cell size and apoptosis of myocytes. Heatmap of multi-omics further showed significant differences between rats with HFpEF and controls. Gene Set Enrichment Analysis (GSEA) of multi-omics revealed genetic risk factors involved in cardiac muscle contraction, proteasome, B cell receptor signaling, and p53 signaling pathway. Gene Ontology (GO) analysis of multi-omics showed the inflammatory response and mitochondrial fission as top biological processes that may deteriorate myocyte stiffening. GO analysis of protein-to-protein network indicated cytoskeleton protein, cell fraction, enzyme binding, and ATP binding as the top enriched molecular functions. Western blot validated upregulated Mff and Itga9 and downregulated Map1lc3a in the HS group, which likely contributed to accumulation of aberrant mitochondria to increase ROS and elevation of myocyte stiffness, and subsequent contractile dysfunction and myocardial apoptosis. (4) Conclusions: Multi-omics analysis revealed multiple pathways associated with HFpEF. This study shows insight into molecular mechanisms for the development of HFpEF and may provide potential targets for the treatment of HFpEF.
（1）背景：由于环境、组织学和遗传风险因素之间的复杂相互作用，射血分数保留的心力衰竭（HFpEF）目前尚无连续治疗方法。本研究旨在研究与 HFpEF 相关的心肌细胞和分子网络的变化。（2）方法：给予 Dahl 盐敏感（DSS）大鼠高盐（HS）饮食 7 周可发展为 HFpEF，通过体内和体外测量进行确认。进一步进行了鸟枪法蛋白质组学、微阵列、Western blot 和定量 RT-PCR 分析，以研究细胞和分子机制。（3）结果：HFpEF 大鼠表现出舒张功能障碍、收缩功能受损和心肌细胞复极化延长，这归因于心肌细胞大小增加和凋亡。多组学热图进一步显示了 HFpEF 大鼠与对照组之间的显著差异。多组学的基因集富集分析（GSEA）显示，心脏肌肉收缩、蛋白酶体、B 细胞受体信号和 p53 信号通路涉及遗传风险因素。多组学的基因本体论（GO）分析显示，炎症反应和线粒体裂变作为可能使心肌变硬恶化的主要生物学过程。蛋白质-蛋白质网络的 GO 分析表明，细胞骨架蛋白、细胞部分、酶结合和 ATP 结合是最丰富的分子功能。Western blot 验证了 HS 组中上调的 Mff 和 Itga9 和下调的 Map1lc3a，这可能导致异常线粒体的积累增加 ROS 和心肌细胞僵硬度的升高，以及随后的收缩功能障碍和心肌细胞凋亡。（4）结论：多组学分析揭示了与 HFpEF 相关的多个途径。本研究深入了解了 HFpEF 发展的分子机制，并可能为 HFpEF 的治疗提供潜在靶点。
