OBJECTIVE Sudden unexpected death in epilepsy (SUDEP) is a major outcome of cardiac dysfunction in patients with epilepsy. In continuation of our previous work, the present study was envisaged to explore the key regulators responsible for cardiac damage associated with chronic seizures using whole transcriptome and proteome analysis in a rat model of temporal lobe epilepsy. METHODS A standard lithium-pilocarpine protocol was used to induce recurrent seizures in rats. The isolated rat heart tissue was subjected to transcriptomic and proteomic analysis. An integrated approach of RNA-Seq, proteomics, and system biology analysis was used to identify key regulators involved in seizure-linked cardiac changes. The analyzed differential expression patterns and network interactions were supported by gene and protein expression studies. RESULTS Altogether, 1157 differentially expressed genes and 1264 proteins were identified in the cardiac tissue of epileptic animals through RNA-Seq and liquid chromatography with tandem mass spectrometry-based proteomic analysis, respectively. The network analysis revealed seven critical genes-STAT3, Myc, Fos, Erbb2, Erbb3, Notch1, and Mapk8-that could play a role in seizure-mediated cardiac changes. The LC-MS/MS analysis supported the activation of the transforming growth factor β (TGF-β) pathway in the heart of epileptic animals. Furthermore, our gene and protein expression studies established a key role of STAT3, Erbb, and Mapk8 to develop cardiac changes linked with recurrent seizures. SIGNIFICANCE The present multi-omics study identified STAT3, Mapk8, and Erbb as key regulators involved in seizure-associated cardiac changes. It provided a deeper understanding of molecular, cellular, and network-level operations of the identified regulators that lead to cardiac changes in epilepsy.

中文翻译：

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通过大鼠模型中的全转录组和蛋白质组分析破译参与癫痫诱导的心脏损伤的关键调节剂

目的 癫痫猝死 (SUDEP) 是癫痫患者心功能不全的主要结果。作为我们之前工作的继续，本研究旨在利用全转录组和蛋白质组分析在颞叶癫痫大鼠模型中探索导致与慢性癫痫发作相关的心脏损伤的关键调节因子。方法 标准的锂-毛果芸香碱方案用于诱导大鼠反复发作。对分离的大鼠心脏组织进行转录组学和蛋白质组学分析。RNA-Seq、蛋白质组学和系统生物学分析的综合方法用于识别与癫痫相关的心脏变化相关的关键调节因子。分析的差异表达模式和网络相互作用得到基因和蛋白质表达研究的支持。结果 总而言之，通过RNA-Seq和液相色谱-串联质谱蛋白质组学分析，分别在癫痫动物的心脏组织中鉴定出1157个差异表达基因和1264个蛋白质。网络分析揭示了七个关键基因——STAT3、Myc、Fos、Erbb2、Erbb3、Notch1 和 Mapk8——它们可能在癫痫介导的心脏变化中发挥作用。LC-MS/MS 分析支持癫痫动物心脏中转化生长因子 β (TGF-β) 通路的激活。此外，我们的基因和蛋白质表达研究确定了 STAT3、Erbb 和 Mapk8 在发展与复发性癫痫发作相关的心脏变化方面的关键作用。意义 目前的多组学研究将 STAT3、Mapk8 和 Erbb 确定为参与癫痫相关心脏变化的关键调节因子。