Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
Mol Cell Biochem. 2023 Jun;478(6):1345-1359. doi: 10.1007/s11010-022-04592-0. Epub 2022 Oct 30.
Alcohol abuse has attracted public attention and long-term alcohol exposure can lead to alcohol-featured non-ischemic dilated cardiomyopathy. However, the precise underlying mechanisms of alcoholic cardiomyopathy remain to be elucidated. This study aimed to comprehensively characterize alcohol abuse-mediated effects on downstream metabolites and genes transcription using a multi-omics strategy. We established chronic ethanol intoxication model in adult male C57BL/6 mice through 8 weeks of 95% alcohol vapor administration and performed metabolomics analysis, mRNA-seq and microRNA-seq analysis with myocardial tissues. Firstly, ethanol markedly induced ejection fraction reductions, cardiomyocyte hypertrophy, and myocardial fibrosis in mice with myocardial oxidative injury. In addition, the omics analysis identified a total of 166 differentially expressed metabolites (DEMs), 241 differentially expressed genes (DEGs) and 19 differentially expressed microRNAs (DEmiRNAs), respectively. The results highlighted that alcohol abuse mainly interfered with endogenous lipids, amino acids and nucleotides production and the relevant genes transcription in mice hearts. Based on KEGG database, the affected signaling pathways are primarily mapped to the antigen processing and presentation, regulation of actin cytoskeleton, AMPK signaling pathway, tyrosine metabolism and PPAR signaling pathway, etc. Furthermore, 9 hub genes related to oxidative stress from DEGs were selected based on function annotation, and potential alcoholic cardiotoxic oxidative stress biomarkers were determined through establishing PPI network and DEmiRNAs-DEGs cross-talk. Altogether, our data strongly supported the conclusion that ethanol abuse characteristically affected amino acid and energy metabolism, nucleotide metabolism and especially lipids metabolism in mice hearts, and underlined the values of lipids signaling and oxidative stress in the treatment strategies.
酒精滥用引起了公众的关注，长期饮酒可导致酒精性非缺血性扩张型心肌病。然而，酒精性心肌病的确切潜在机制仍有待阐明。本研究旨在采用多组学策略全面描述酒精滥用对下游代谢物和基因转录的影响。我们通过 8 周 95%酒精蒸气给药在成年雄性 C57BL/6 小鼠中建立慢性乙醇中毒模型，并对心肌组织进行代谢组学分析、mRNA-seq 和 microRNA-seq 分析。首先，乙醇显著诱导了伴有心肌氧化损伤的小鼠射血分数降低、心肌细胞肥大和心肌纤维化。此外，组学分析共鉴定出 166 个差异表达代谢物（DEMs）、241 个差异表达基因（DEGs）和 19 个差异表达 microRNAs（DEmiRNAs）。结果表明，酒精滥用主要干扰了小鼠心脏内源性脂质、氨基酸和核苷酸的产生及其相关基因的转录。基于 KEGG 数据库，受影响的信号通路主要映射到抗原加工和呈递、肌动蛋白细胞骨架调节、AMPK 信号通路、酪氨酸代谢和 PPAR 信号通路等。此外，根据功能注释从 DEGs 中选择了 9 个与氧化应激相关的枢纽基因，并通过建立 PPI 网络和 DEmiRNAs-DEGs 相互作用确定了潜在的酒精性心脏毒性氧化应激生物标志物。总之，我们的数据有力地支持了这样的结论，即乙醇滥用显著影响了小鼠心脏中的氨基酸和能量代谢、核苷酸代谢，特别是脂质代谢，并强调了脂质信号和氧化应激在治疗策略中的价值。
