Miao Weilun, Shi Jiaojiao, Huang Jiayi, Lin Yongpin, Cui Chang, Zhu Yue, Zheng Bingyu, Li Mingfang, Jiang Qi, Chen Minglong
Department of Cardiology, Huashan Hospital Affiliated to Fudan University, Shanghai 200000, China.
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China.
Stem Cell Res. 2022 Apr;60:102686. doi: 10.1016/j.scr.2022.102686. Epub 2022 Jan 24.
Hypoglycemicagents have been shown to reduce the incidence of atrial fibrillation (AF) in patients with diabetes mellitus. Azoramide is a novel anti-diabetic agent which protects cells against endoplasmic reticulum (ER) stress; however, the cardioprotective effect of azoramide against AF is not clear. In this study, we aimed to investigate the protective effect of azoramide in human iPS-derived atrial myocytes (a-iCMs) against injury induced by high-frequency electrical stimulation. Human-induced pluripotent stem cells were differentiated into a-iCMs by treatment of retinoic acid. The tachypacing group was subjected to 7 Hz tachypacing for 48 h. Azoramide was preconditioned 2-hours before tachypacing. a-iCMs expressed atria-specific genes and the characteristics of the action potential were analogous to those of human atrial myocytes. Tachypacing induced disorder of intracellular calcium homeostasis, apoptosis, depressed ATP level, and severer myofilament dissolution. MetaboAnalysis revealed that tachypacing induced remarkable changes in metabolites involved in energy, amino acid, and glucose metabolism, whereas there was no significant effect on lipid metabolism. Azoramide pretreatment partly alleviated tachypacing-induced calcium dyshomeostasis, ATP consumption, and accelerated apoptosis, which was likely achieved by regulating the PERK/CHOP/CaMKII pathway. Azoramide protected atrial myocytes against injury induced by high-frequency electrical stimulation by regulating ER stress, which may inhibit cell apoptosis and calcium dyshomeostasis via the PERK/CHOP/CaMKII pathway.
降糖药物已被证明可降低糖尿病患者心房颤动（AF）的发生率。阿佐酰胺是一种新型抗糖尿病药物，可保护细胞免受内质网（ER）应激；然而，阿佐酰胺对AF的心脏保护作用尚不清楚。在本研究中，我们旨在研究阿佐酰胺对人诱导多能干细胞来源的心房肌细胞（a-iCMs）免受高频电刺激诱导损伤的保护作用。通过视黄酸处理将人诱导多能干细胞分化为a-iCMs。快速起搏组接受7Hz快速起搏48小时。阿佐酰胺在快速起搏前2小时进行预处理。a-iCMs表达心房特异性基因，动作电位特征与人心房肌细胞相似。快速起搏诱导细胞内钙稳态紊乱、细胞凋亡、ATP水平降低和更严重的肌丝溶解。代谢分析显示，快速起搏诱导参与能量、氨基酸和葡萄糖代谢的代谢物发生显著变化，而对脂质代谢无显著影响。阿佐酰胺预处理部分减轻了快速起搏诱导的钙稳态失调、ATP消耗和加速的细胞凋亡，这可能是通过调节PERK/CHOP/CaMKII途径实现的。阿佐酰胺通过调节内质网应激保护心房肌细胞免受高频电刺激诱导的损伤，这可能通过PERK/CHOP/CaMKII途径抑制细胞凋亡和钙稳态失调。
