Table3_Transcriptional changes during isoproterenol-induced cardiac fibrosis in mice.XLSX

Introduction: β-adrenergic stimulation using β-agonists such as isoproterenol has been routinely used to induce cardiac fibrosis in experimental animal models. Although transcriptome changes in surgical models of cardiac fibrosis such as transverse aortic constriction (TAC) and coronary artery ligation (CAL) are well-studied, transcriptional changes during isoproterenol-induced cardiac fibrosis are not well-explored.
Methods: Cardiac fibrosis was induced in male C57BL6 mice by administration of isoproterenol for 4, 8, or 11 days at 50 mg/kg/day dose. Temporal changes in gene expression were studied by RNA sequencing.
Results and discussion: We observed a significant alteration in the transcriptome profile across the different experimental groups compared to the saline group. Isoproterenol treatment caused upregulation of genes associated with ECM organization, cell–cell contact, three-dimensional structure, and cell growth, while genes associated with fatty acid oxidation, sarcoplasmic reticulum calcium ion transport, and cardiac muscle contraction are downregulated. A number of known long non-coding RNAs (lncRNAs) and putative novel lncRNAs exhibited differential regulation. In conclusion, our study shows that isoproterenol administration leads to the dysregulation of genes relevant to ECM deposition and cardiac contraction, and serves as an excellent alternate model to the surgical models of heart failure.

引言：采用异丙肾上腺素（isoproterenol）等β肾上腺素受体激动剂（β-agonists）进行β肾上腺素能刺激，是实验动物模型中诱导心脏纤维化的经典常规方法。尽管主动脉弓缩窄（transverse aortic constriction, TAC）、冠状动脉结扎（coronary artery ligation, CAL）等心脏纤维化手术模型的转录组变化已得到充分研究，但异丙肾上腺素诱导的心脏纤维化过程中的转录组变化尚未得到深入探究。
方法：通过以50mg/kg/天的剂量对雄性C57BL6小鼠连续给药异丙肾上腺素，分别给药4、8或11天，以构建心脏纤维化模型。采用RNA测序技术分析基因表达的时序变化特征。
结果与讨论：与生理盐水对照组相比，各实验组的转录组谱均发生显著改变。异丙肾上腺素处理可上调与细胞外基质（extracellular matrix, ECM）组织、细胞间连接、三维结构及细胞生长相关的基因表达，同时下调与脂肪酸氧化、肌浆网钙离子转运及心肌收缩相关的基因表达。多种已知长链非编码RNA（long non-coding RNAs, lncRNAs）及潜在新型长链非编码RNA均呈现出差异表达调控特征。综上，本研究证实，异丙肾上腺素给药会导致与细胞外基质沉积及心肌收缩相关的基因表达失调，该模型可作为心力衰竭手术模型的优质替代模型。