Chronic ethanol exposure induces mitochondrial dysfunction and alters gene expression and metabolism in human cardiac spheroids
Chronic ethanol exposure induces mitochondrial dysfunction and alters gene expression and metabolism in human cardiac spheroids
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DOI：
10.1111/acer.15026
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发表时间：
2023-02-17
期刊：
影响因子：
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通讯作者：
Xu，Chunhui
中科院分区：
文献类型：
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作者：
Hwang，Hyun;Liu，Rui;Xu，Chunhui
研究背景成年人长期饮酒可引起心律失常、心肌病和心力衰竭等多种心脏毒性。产前酒精暴露会增加后代患先天性心脏病的风险。了解长期酒精暴露诱导的心脏毒性的分子机制可以帮助指导治疗策略的发展。MethodsCardiomyocytes来自人诱导多能干细胞（hiPSC-CMs）被设计成心脏球体，并与临床相关浓度的乙醇（17和50 mM）治疗5周。然后分析细胞的线粒体特征，转录组学和代谢组学特征的变化，以及整合的组学outcomes. ResultsAfter慢性乙醇处理hiPSC-CM，线粒体膜电位和呼吸降低，线粒体功能相关基因的表达变化被观察到。RNA测序分析揭示了各种代谢过程、心脏发育、缺氧反应和细胞外基质相关活动的变化。代谢组学分析揭示了能量代谢的失调和与炎症上调相关的代谢物增加。综合组学分析进一步确定了功能亚群，并揭示了可能受影响的途径与心脏toxicity.ConclusionChronic乙醇治疗hiPSC-CM导致整体线粒体功能下降，增加糖酵解，破坏脂肪酸氧化，心脏结构发育受损。
BackgroundChronic alcohol consumption in adults can induce various cardiac toxicities such as arrhythmias, cardiomyopathy, and heart failure. Prenatal alcohol exposure can increase the risk of developing congenital heart defects among offspring. Understanding the molecular mechanisms underlying long‐term alcohol exposure‐induced cardiotoxicity can help guide the development of therapeutic strategies.MethodsCardiomyocytes derived from human‐induced pluripotent stem cells (hiPSC‐CMs) were engineered into cardiac spheroids and treated with clinically relevant concentrations of ethanol (17 and 50 mM) for 5 weeks. The cells were then analyzed for changes in mitochondrial features, transcriptomic and metabolomic profiles, and integrated omics outcomes.ResultsFollowing chronic ethanol treatment of hiPSC‐CMs, a decrease in mitochondrial membrane potential and respiration and changes in expression of mitochondrial function‐related genes were observed. RNA‐sequencing analysis revealed changes in various metabolic processes, heart development, response to hypoxia, and extracellular matrix‐related activities. Metabolomic analysis revealed dysregulation of energy metabolism and increased metabolites associated with the upregulation of inflammation. Integrated omics analysis further identified functional subclusters and revealed potentially affected pathways associated with cardiac toxicities.ConclusionChronic ethanol treatment of hiPSC‐CMs resulted in overall decreased mitochondrial function, increased glycolysis, disrupted fatty acid oxidation, and impaired cardiac structural development.