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Abstract：
Interconnected mechanisms of ischemia and reperfusion (IR) has increased the interest in IR in vitro experiments using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We developed a whole-cell computational model of hiPSC-CMs including the electromechanics, a metabolite-sensitive sarcoplasmic reticulum Ca2+-ATPase (SERCA) and an oxygen dynamics formulation to investigate IR mechanisms. Moreover, we simulated the effect and action mechanism of levosimendan, which recently showed promising anti-arrhythmic effects in hiPSC-CMs in hypoxia. The model was validated using hiPSC-CM and in vitro animal data. The role of SERCA in causing relaxation dysfunction in IR was anticipated to be comparable to its function in sepsis-induced heart failure. Drug simulations showed that levosimendan counteracts the relaxation dysfunction by utilizing a particular Ca2+-sensitizing mechanism involving Ca2+-bound troponin C and Ca2+ flux to the myofilament, rather than inhibiting SERCA phosphorylation. The model demonstrates extensive characterization and promise for drug development, making it suitable for evaluating IR therapy strategies based on the changing levels of cardiac metabolites, oxygen and molecular pathways.
摘要：
缺血和再灌注（IR）的相互关联的机制增加了对使用人诱导的多能干细胞衍生的心肌细胞（hiPSC-CM）进行IR体外实验的兴趣。我们开发了hiPSC-CM的全细胞计算模型，包括机电，代谢物敏感的肌浆网Ca2+-ATPase（SERCA）和氧动力学制剂来研究IR机制。此外，我们模拟了左西孟旦的作用和作用机制，最近在缺氧的hiPSC-CM中显示出有希望的抗心律失常作用。使用hiPSC-CM和体外动物数据验证模型。预计SERCA在引起IR舒张功能障碍中的作用与其在脓毒症诱导的心力衰竭中的功能相当。药物模拟表明，左西孟旦通过利用涉及Ca2结合的肌钙蛋白C和Ca2流向肌丝的特定Ca2敏化机制来抵消松弛功能障碍，而不是抑制SERCA磷酸化。该模型展示了广泛的表征和药物开发的前景，使其适合根据心脏代谢物水平的变化评估IR治疗策略，氧和分子途径。
