Waleczek Florian J G, Cipriano Giuseppe, Haas Jonas A, Garg Ankita, Pfanne Angelika, Just Annette, Neumüller Susanne, Hegermann Jan, Pich Andreas, Radocaj Ante, Xiao Ke, Weber Natalie, Thum Thomas
Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, 30625 Hannover, Germany.
Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany.
Int J Mol Sci. 2024 Dec 30;26(1):218. doi: 10.3390/ijms26010218.
Ischemic heart disease is the leading cause of death worldwide. Reduced oxygen supply and myocardial hypoxia lead to tissue damage and impairment of the heart function. To the best of our knowledge, the primary functional effects of hypoxia in the multicellular model of living myocardial slices (LMSs) have not been investigated so far. In this study, we analyzed force generation, ultrastructure, gene expression, and proteome changes in rat LMS after 24 h of ex vivo culture in normal and reduced levels of oxygen (O). We observed a significant reduction in absolute force and a slowdown of force kinetics as well as an increase in cardiomyocyte apoptosis and myofibrillar and mitochondrial damage, as well as transcriptomic changes. Proteome analysis revealed the deregulation of proteins involved in metabolic processes, hypoxic response, and neutralizing of reactive oxygen species. Our results indicate that hypoxia induces substantial primary changes in heart tissue, which are independent of perfusion and immune responses. Our new LMS model could serve as a screening system for drug development and new mechanistic insights.
缺血性心脏病是全球主要的死亡原因。氧气供应减少和心肌缺氧会导致组织损伤和心脏功能受损。据我们所知，到目前为止尚未研究缺氧在活心肌切片（LMS）多细胞模型中的主要功能影响。在本研究中，我们分析了在正常氧水平和低氧水平（O）下离体培养24小时后大鼠LMS中的力产生、超微结构、基因表达和蛋白质组变化。我们观察到绝对力显著降低、力动力学减慢以及心肌细胞凋亡增加、肌原纤维和线粒体损伤，以及转录组变化。蛋白质组分析揭示了参与代谢过程、低氧反应和活性氧中和的蛋白质失调。我们的结果表明，缺氧会在心脏组织中引起实质性的原发性变化，这些变化与灌注和免疫反应无关。我们新的LMS模型可作为药物开发和新机制见解的筛选系统。
