Morphometric, Hemodynamic, and Multi-Omics Analyses in Heart Failure Rats with Preserved Ejection Fraction
Morphometric, Hemodynamic, and Multi-Omics Analyses in Heart Failure Rats with Preserved Ejection Fraction
复制标题
射血分数保留的心力衰竭大鼠的形态、血流动力学和多组学分析
DOI：
10.3390/ijms21093362
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发表时间：
2020-05-01
影响因子：
5.6
通讯作者：
Tan, Wenchang
中科院分区：
文献类型：
--
作者：
Zhang, Wenxi;Zhang, Huan;Tan, Wenchang
(1)背景资料：由于环境、组织学和遗传风险因素之间的复杂相互作用，射血分数保留性心力衰竭（HFpEF）没有连续的治疗方法。本研究的目的是研究与HFpEF相关的心肌细胞和分子网络的变化。(2)研究方法：Dahl盐敏感（DSS）大鼠在喂食高盐（HS）饮食7周后发生HFpEF，这一点通过体内和体外测量得到证实。进一步利用鸟枪蛋白质组学、基因芯片、蛋白质印迹和定量RT-PCR等技术研究其细胞和分子机制。(3)结果如下：HFpEF大鼠表现出舒张功能障碍，收缩功能受损，和延长复极的心肌细胞，由于细胞大小和细胞凋亡的增加。多组学热图进一步显示HFpEF大鼠与对照组之间存在显著差异。多组学的基因集富集分析（GSEA）揭示了涉及心肌收缩、蛋白酶体、B细胞受体信号和p53信号通路的遗传危险因素。多组学的基因本体论（GO）分析显示，炎症反应和线粒体分裂是可能恶化肌细胞硬化的最重要的生物过程。蛋白质-蛋白质网络的GO分析表明，细胞骨架蛋白、细胞组分、酶结合和ATP结合是最富集的分子功能。Western blot证实HS组中Mff和Itga 9上调，Map 1 lc 3a下调，这可能有助于异常线粒体的积累，增加ROS和心肌细胞刚度的升高，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HFpEF相关的多个通路。本研究揭示了HFpEF发生的分子机制，并可能为HFpEF的治疗提供潜在的靶点。
(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.